Cannabigerol derivatives and use thereof as cannabinoid receptor modulators

ABSTRACT

The synthesis of a range of pentylbezene-1,3-diol compounds of formula I is disclosed. These compounds bind to cannabinoid 1 and 2 receptors (CB1 and CB2), and are thus presumed to be useful in modulating the activity of such receptors. Accordingly, the use of such synthetic cannabinoids in the treatment of various disorders mediated by CB1 and CB2 is contemplated.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and benefit of U.S. Provisional Pat.Application Serial Number 62/940,545 filed on Nov. 26, 2019 and U.S.Provisional Pat. Application Serial Number 63/110,479 filed on Nov. 6,2020, each of which is hereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

This disclosure relates generally to cannabinoid derivatives,pharmaceutical compositions comprising them, and methods of using thecannabinoid derivatives.

TECHNICAL BACKGROUND

Every individual has an endocannabinoid system comprised of chemicalreceptors in the brain, immune system, and central nervous system, forexample including the cannabinoid 1 (CB1) receptor and cannabinoid 2(CB2) receptor. The endocannabinoid system regulates many importantphysiological processes and several components of the endocannabinoidsystem, such as receptors, transporters, endocannabinoids and enzymesinvolved in the synthesis and degradation of endocannabinoids, are underactive investigation as targets to treat a diverse array of indications.

CB1 and CB2 receptors are a class of cell membrane receptors belongingto the G protein-coupled receptor (GPCR) superfamily. The CB1 and CB2receptors are distinguished from each other by their amino acidsequence, tissue distribution, signaling mechanisms, and ability to bindsub-type specific ligands. The CB1 receptor is mainly expressed in thecentral nervous system (CNS), lungs, liver, adipose tissue, and kidneys,and the CB2 receptor is mainly localized in immune cells (e.g.macrophages and T-cells), on cells that are involved in bone formationand bone loss, and in the gastrointestinal system. These receptors havebeen associated with many human diseases including obesity, diabetes,fibrosis, liver diseases, cardiovascular disease, cancer, pain,inflammation, MS spasticity, and glaucoma, among others.

Cannabinoids are compounds active on cannabinoid receptors in humans andhave been implicated in many of the pharmacological benefits on thediseases noted above. Cannabinoids of plant origin, also known asphytocannabinoids, are abundant in Cannabis. Medical use of cannabis andassociated phytocannabinoids is becoming widely accepted in manycountries, including the United States, as an alternative form ofmedicine. Many states have legalized its use for qualified medicalconditions such as chronic pain, epilepsy, sleep disorders, anxiety,cancer, glaucoma, nausea, amyotrophic lateral sclerosis (ALS),Alzheimer’s disease, Crohn’s disease, Post-traumatic Stress Disorder(PTSD), arthritis, fibromyalgia, and others.

In addition to the CB1 and CB2 receptors, other receptors have also beenimplicated in modulating the activity of cannabinoids in the humanand/or animal body. For example, the serotonin receptors, such as 5HT1Aand 5HT2A, are likewise GPCRs that have been identified as cannabinoidtargets. The serotonin receptors modulate the release of manyneurotransmitters, including glutamate, GABA, dopamine,epinephrine/norepinephrine and acetylcholine, as well as many hormones.Like the CB1 and CB2 receptors, the serotonin receptors influencevarious biological and neurological processes, such as anxiety,appetite, cognition, and mood, among others. Other receptors identifiedas being influenced by cannabinoid or cannabinoid-like compounds includeGPR18, GPR55, GPR119, TRPV1, TPRV2, PPARs (e.g. PPAR_(γ)), and theµ-opioid receptors. Indeed, binding of these receptors may beresponsible for off-target effects of cannabinoids.

One of the most common ways that cannabinoids are used for medicinal usein many countries is through smoking of cannabis. Although proven to bebeneficial in certain indications, smoking medical cannabis hasdisadvantages. For example, the smoke from the plant matter comprisescarcinogens and other toxins in addition to the desired cannabinoids.Heavy cannabis use through smoking has also been associated withaccelerated pulmonary decline, lung damage, and emphysema. Anotherdisadvantage of smoking medical cannabis is difficulty in maintainingcontrol over the proper dosing of medicinal cannabis due to activeingredients fluctuations (e.g., the amounts of active ingredients maydiffer depending on the differences present in plant varietals as wellas changing growing conditions which result in intravarietalvariations). Finally, consumption through smoking has a relatively lowbioavailability of target compounds compared to other delivery methods.

A less common way to utilize cannabis for medical use is to extractbeneficial cannabinoids from cannabis. Many extraction processes havebeen developed for isolating and purifying natural cannabinoids. Butthere has been difficulty in isolating individual cannabinoids at highlevels of purity, both for active ingredients for use in medicine andproduct manufacturing and/or as standards for use in research anddevelopment.

Therefore, there exists a need for novel ligands of cannabinoidreceptors that have the potential for therapeutic benefit.

SUMMARY OF THE DISCLOSURE

One aspect of the present disclosure relates to compounds of formula(I):

or an enantiomer, diastereomer, racemate, tautomer, or metabolitethereof, or of a pharmaceutically acceptable salt, a solvate or hydrateof the compound, enantiomer, diastereomer, racemate, tautomer, ormetabolite, wherein

-   R¹ is hydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    -CO₂H, -(C₀-C₄ alkyl)-C(O)O(C₁-C₆ alkyl), -(C₀-C₄    alkyl)-OC(O)O-(C₁-C₆ alkyl), -(C₀-C₄ alkyl)-N(R^(1b))-C(O)-O-(C₁-C₆    alkyl), -(C₀-C₄ alkyl)-O-C(O)-NR^(1b)R^(1c), -(C₀-C₄    alkyl)-N(R^(1b))-C(O)-NR^(1b)R^(1c), -OR^(1a), -(C₁-C₄    alkyl)OR^(1a), -SR^(1a), -(Ci-C₄alkyl)S(O)₀₋₂R^(1a), -NR^(1b)R^(1c),    -(C₁-C₄ alkyl)NR^(1b)R^(1c), -(C₁-C₄ alkyl)C(O)NR^(1b)R^(1c),    -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl, wherein    R^(1a), R^(1b), and R^(1c) are independently hydrogen, C₁-C₄ alkyl,    or -C(O)(C₁-C₄) alkyl;

-   R² is hydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    -CO₂H, -(C₀-C₄ alkyl)-C(O)O(C₁-C₆ alkyl), -(C₀-C₄    alkyl)-OC(O)O-(C₁-C₆ alkyl), -(C₁-C₄ alkyl)OR^(2a), -(C₁-C₄    alkyl)SR^(2a), -NR^(2b)R^(2c), -(C₁-C₄ alkyl)NR^(2b)R^(2c), -(C₁-C₄    alkyl)C(O)NR^(2b)R^(2c), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄    alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, or -(C₀-C₄    alkyl)-heterocycloalkyl, wherein    -   R^(2a), R^(2b), and R^(2c) are independently hydrogen, C₁-C₄        alkyl, or -C(O)(C₁-C₄) alkyl;

-   R³ is hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,    -(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), -(C₀-C₄ alkyl)-NR^(3a)R^(3b), -(C₀-C₄    alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl or    -(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(3a) and R^(3b) are each    independently hydrogen or C₁-C₆ alkyl;

-   

-   

-   or

-   

-   wherein

-   R^(4a) is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, -OR^(4e),    -(C₁-C₄ alkyl)OR^(4e), -(C₁-C₄ alkyl)-C(O)(C₁-C₄ alkyl), -(C₀-C₄    alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl,    -(C₀-C₄ alkyl)-heterocycloalkyl, -NR^(4d)R^(4e), or -(C₁-C₄    alkyl)NR^(4d)R^(4e), and

-   R^(4b) is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,    -CH₂-(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), -(C₁-C₄ alkyl)OR^(4e), -(C₁-C₄    alkyl)-C(O)(C₁-C₄ alkyl), -(C₁-C₄ alkyl)-C(O)O(R^(4e)), -(C₀-C₄    alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl,    -(C₀-C₄ alkyl)-heterocycloalkyl, or -(C₁-C₄ alkyl)NR^(4d)R^(4e),    wherein    -   R^(4d) is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, -(C₁-C₄        alkyl)-C(O)(C₁-C₄ alkyl), -(C₁-C₄ alkyl)-C(O)O(R^(4e)), -(C₁-C₄        alkyl)-OC(O)(R^(4e)), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄        alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, or -(C₀-C₄        alkyl)-heterocycloalkyl,    -   R^(4e) is hydrogen, C₁-C₄ alkyl, or aryl, and

-   R^(4c) is hydrogen or C₁-C₄ alkyl;

-   R⁵ is hydrogen, C₁-C₈ alkyl, -(C₁-C₄ alkyl)-O-(C₁-C₄ alkyl),    -C(O)(C₁-C₄ alkyl), -C(O)O(C₁-C₄ alkyl), -C(O)NH₂, -C(O)NH(C₁-C₄    alkyl), -C(O)N(C₁-C₄ alkyl)₂, -(C₁-C₄ alkyl)C(O)O(C₁-C₄ alkyl), or    -(C₁-C₄ alkyl)OC(O)(C₁-C₄ alkyl); and

-   R⁶ is hydrogen or -OR^(6a), wherein R^(6a) is hydrogen, C₁-C₈ alkyl,    -(C₁-C₄ alkyl)-O-(C₁-C₄ alkyl), -C(O)(C₁-C₄ alkyl), -C(O)O(C₁-C₄    alkyl), -C(O)NH₂, -C(O)NH(C₁-C₄ alkyl), -C(O)N(C₁-C₄ alkyl)₂,    -(C₁-C₄ alkyl)C(O)O(C₁-C₄ alkyl), or -(C₁-C₄ alkyl)OC(O)(C₁-C₄    alkyl); wherein    -   each alkyl, alkenyl and alkynyl is unsubstituted, halogenated        (e.g., fluorinated, chlorinated), substituted with one or two        hydroxyl or C₁-C₆ alkoxy groups, or substituted with one or two        oxo groups;    -   each cycloalkyl has 3-10 ring carbons and is saturated or        partially unsaturated, and optionally includes one or two fused        cycloalkyl rings, each fused ring having 3-8 ring members, and        is substituted with 0-6 R⁷;    -   each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms        where each is independently nitrogen, oxygen or sulfur and is        saturated or partially unsaturated, and optionally includes one        or two fused cycloalkyl rings, each having 3-8 ring members, and        is substituted with 0-6 R⁷;    -   each aryl is a phenyl or a naphthyl, and optionally includes one        or two fused cycloalkyl or heterocycloalkyl rings, each fused        cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and        is substituted with 0-5 R⁸;    -   each heteroaryl is a 5-6 membered monocyclic heteroaryl ring        having 1-4 heteroatoms, where each is independently nitrogen,        oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having        1-5 heteroatoms where each is independently nitrogen, oxygen or        sulfur, and optionally includes one or two fused cycloalkyl or        heterocycloalkyl rings, each fused cycloalkyl or        heterocycloalkyl ring having 4- 8 ring members, and is        substituted with 0-5 R⁸, in which        -   each R⁷ is independently oxo, C₁-C₄ alkyl, -Cl, -F, -Br,            -CN, -SF₅, -N₃, nitro, -SR^(A), -S(O)₁₋₂R^(A), -OR^(A),            -(C₀-C₃ alkyl)-OR^(B), -NR^(B)R^(A), -C(O)R^(A),            -C(O)NR^(B)R^(A), -NR^(B)C(O)R^(A), -C(S)NR^(B)R^(A),            -NR^(B)C(S)R^(A), -CO2R^(A), -OC(O)R^(A), -C(O)SR^(A),            -SC(O)R^(A), -C(S)OR^(A), -OC(S)R^(A), -C(S)SR^(A),            -SC(S)R^(A), -S(O)1-2OR^(A), -OS(O)1-2R^(A),            -S(O)₁₋₂NR^(B)R^(A), -NR^(B)S(O)₁₋₂R^(A), -OCO₂R^(A),            -OC(O)NR^(B)R^(A), -NR^(B)CO₂R^(A), -NR^(B)C(O)NR^(B)R^(A),            -SCO₂R^(A), -OC(O)SR^(A), -SC(O)SR^(A), -SC(O)NR^(B)R^(A),            -NR^(B)C(O)SR^(A), -OC(S)OR^(A), -OC(S)NR^(B)R^(A),            -NR^(B)C(S)OR^(A), -NR^(B)C(S)NR^(B)R^(A), -SC(S)OR^(A),            -OC(S)SR^(A), -SC(S)SR^(A), -SC(S)NR^(B)R^(A),            -NR^(B)C(S)SR^(A), -NR^(B)C(NR^(B))NR^(B)R^(A),            -NR^(B)S(O)₁₋₂NR^(B)R^(A), phenyl, C₃-C₈ cycloalkyl, a five            to six-membered heteroaryl, or a five to six-membered            heterocycloalkyl; and        -   each R⁸ is independently optionally-substituted C₁-C₄ alkyl,            -Cl, -F, -Br, -CN, -SF₅, -N₃, nitro, -SR^(A), -S(O)₁₋₂R^(A),            -OR^(A), -(C₀-C₃ alkyl)-OR^(B), -NR^(B)R^(A), -C(O)R^(A),            -C(O)NR^(B)R^(A), -NR^(B)C(O)R^(A), -C(S)NR^(B)R^(A),            -NR^(B)C(S)R^(A), -CO₂R^(A), -OC(O)R^(A),-SO₃H,-C(O)SR^(A),            -SC(O)R^(A), -C(S)OR^(A), -OC(S)R^(A), -C(S)SR^(A),            -SC(S)R^(A), -S(O)₁₋₂OR^(A), -OS(O)₁₋₂R^(A),            -S(O)₁₋₂NR^(B)R^(A), -NR^(B)S(O)₁₋₂R^(A), -OCO₂R^(A),            -OC(O)NR^(B)R^(A), -NR^(B)CO₂R^(A), -NR^(B)C(O)NR^(B)R^(A),            -SCO₂R^(A), -OC(O)SR^(A), -SC(O)SR^(A), -SC(O)NR^(B)R^(A),            -NR^(B)C(O)SR^(A), -OC(S)OR^(A), -OC(S)NR^(B)R^(A),            -NR^(B)C(S)OR^(A), -NR^(B)C(S)NR^(B)R^(A), -SC(S)OR^(A),            -OC(S)SR^(A), -SC(S)SR^(A), -SC(S)NR^(B)R^(A),            -NR^(B)C(S)SR^(A), -NR^(B)C(NR^(B))NR^(B)R^(A),            -NR^(B)S(O)₁₋₂NR^(B)R^(A); phenyl, C₃-C₈ cycloalkyl, a five            to six-membered heteroaryl, or a five to six-membered            heterocycloalkyl;        -   wherein each R^(A) is independently H or C₁-C₃ alkyl, and            each R^(B) is independently H, C₁-C₃ alkyl, C₁-C₃            fluoroalkyl, C₁-C₃ hydroxyalkyl, -S(O)₁-₂(C₁-C₃ alkyl),            -C(O)(C₁-C₃ alkyl) or-CO₂(C₁-C₃ alkyl), or R^(A) and            R^(B)together with the nitrogen atom to which they are            attached come together to form an unsubstituted            heterocycloalkyl ring comprised of 3-6 ring members.

In another aspect, the present disclosure relates to pharmaceuticalcompositions comprising a compound (e.g., a compound of formula (I)) asdescribed herein, or an enantiomer, diastereomer, racemate, tautomer, ormetabolite thereof, or a pharmaceutically acceptable salt, solvate orhydrate of the compound, enantiomer, diastereomer, racemate, tautomer,or metabolite. In an embodiment, the pharmaceutical compositionscomprise a pharmaceutically acceptable excipient, diluent, or carrier.

In another aspect, the present disclosure relates to a method fortreating or preventing a disease, such as a disease associated with acannabinoid 1 receptor (e.g. CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55,GPR119, TRPV1, TPRV2, PPARγ, or a µ-opioid receptor), in a subject inneed thereof. In an embodiment, the method includes administering to thesubject a therapeutically effective amount of a compound as describedherein, or an enantiomer, diastereomer, racemate, tautomer, ormetabolite thereof, or a pharmaceutically acceptable salt, solvate orhydrate of the compound, enantiomer, diastereomer, racemate, tautomer,or metabolite. In an embodiment, the method includes administering tothe subject a pharmaceutical composition as described herein.

In certain embodiments, the diseases that may be treated or preventedwith the compounds or compositions as described herein include, but arenot limited to attention-deficit/hyperactivity disorder (ADHD)/attention-deficit disorder (ADD), alcohol use disorder, allergic asthma,amyotrophic lateral sclerosis (ALS), Alzheimer’s, anorexia (e.g. humanimmunodeficiency virus (HIV)-related cachexia), anxiety disorders (e.g.,social anxiety disorder, specific phobia, test anxiety, generalizedanxiety disorder), arthritis, atherosclerosis, autism, bipolar disorder,burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronicinflammatory demyelinating polyneuropathies, chronic allograftnephropathy, cocaine use disorder, complex regional pain syndrome,congestive heart failure, depression, fibromyalgia, fragile Xsyndrome/fragile X-associated tremor and ataxia syndrome (FXTAS),frontotemporal dementias (behavioural variant), gingivitis pyrexia,glaucoma, glioblastoma, glomerulonephropathy, Huntington’s disease,hypertrophic scars, inflammatory bowel disease (IBD)/ irritable bowelsyndrome (IBS), inflammation, Inflammatory myopathies, ischemia, kidneyfibrosis, keloids, leukodystrophies, liver fibrosis, liver cirrhosis,lung fibrosis, migraine, multiple sclerosis, myocardial infarction,nausea (e.g. chemotherapy-induced nausea and vomiting (CINV), motionsickness), neuropathic pain (e.g., postherpetic neuralgia, painfuldiabetic neuropathy), nightmare disorder, non-alcoholic fatty liverdisease, obesity, obsessive-compulsive disorder, opioid sparing, opioiduse disorder, osteoarthritis, osteoporosis, pain (e.g. acute or chronicpain), Parkinson’s, post -concussion syndrome/traumatic brain injury,psychosis/schizophrenia, posttraumatic stress disorder (PTSD),regulation of bone mass, rapid eye movement (REM) sleep behaviourdisorder, reperfusion injury, Rett syndrome, rheumatoid arthritis, skinconditions (e.g. acne, psoriatic arthritis), sleep disorders (e.g.,insomnia, restless legs syndrome (RLS)), spinocerebellar ataxias,systemic fibrosis, systemic sclerosis, thermal injury, tobacco usedisorder/nicotine dependence, Tourette’s, tumors, and trigeminalneuralgia.

In another aspect, the present disclosure relates to use of a compoundas described herein, or an enantiomer, diastereomer, racemate, tautomer,or metabolite thereof, or a pharmaceutically acceptable salt, solvate orhydrate of the compound, enantiomer, diastereomer, racemate, tautomer,or metabolite, for the treatment or prevention of a disease associatedwith a cannabinoid receptor (e.g. CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55,GPR119, TRPV1, TPRV2, PPARγ, or a µ-opioid receptor).

In another aspect, the present disclosure relates to use of apharmaceutical composition as described herein for the treatment orprevention of a disease associated with a cannabinoid receptor (e.g.CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARγ, or aµ-opioid receptor).

In another aspect, the present disclosure relates to use of a compoundas described herein, or an enantiomer, diastereomer, racemate, tautomer,or metabolite thereof, or a pharmaceutically acceptable salt, solvate orhydrate of the compound, enantiomer, diastereomer, racemate, tautomer,or metabolite, for selectively modulating the activity of a CB1 or CB2receptor.

In another aspect, the present disclosure relates to use of apharmaceutical composition as described herein, for selectivelymodulating the activity of a CB1 or CB2 receptor.

Other aspects and embodiments of the disclosure are evident in view ofthe detailed description provided herein.

DETAILED DESCRIPTION

The present disclosure provides compounds capable of acting as ligandsto one or more cannabinoid receptors and/or prodrugs thereof. As usedherein, “cannabinoid receptor” refers to a broad class of receptors thatbind, interact with and/or are influenced functionally by cannabinoidsor cannabinoid-like compounds. Without limitation, cannabinoid receptorsmay include CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2,PPARs (e.g. PPARγ) or µ-opioid receptors. In an embodiment, the presentdisclosure further relates to compounds, pharmaceutical compositions,methods and uses having the potential for treating or preventing one ormore diseases associated with a cannabinoid receptor.

The compounds of the present disclosure can be defined generically aswith respect to formula (I) as appropriate,

or in various subgenera compounds in which within the structural formula(I), R¹, R², R³, R⁵, R⁶, R⁴, and R^(4a), R^(4b), and R^(4c) areoptionally independently selected from the groups (la) to (le), (1a) to(1q) , (2a) to (2s), (3a) to (3p), (4a) to (4c), (5a) to (5e), (6a) to(6e), and (7a) to (7gg) defined herein below (e.g., wherein the compoundis of a structural formula as defined in any combination of theembodiments below):

In certain embodiments of the compounds as otherwise described herein,R¹ is selected from one of the following groups (1a) - (1q):

-   (1a) hydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, -CO₂H, -(C₀-C₄    alkyl)-C(O)O(C₁-C₆ alkyl), -OR^(1a), -(C₁-C₄ alkyl)OR^(1a),    -SR^(1a), -(C₁-C₄alkyl)SR^(1a), -NR^(1b)R^(1c), -(C₁-C₄    alkyl)NR^(1b)R^(1c), -(C₁-C₄ alkyl)C(O)NR^(1b)R^(1c),-(C₀-C₄    alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl,    or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (1b) The compound according to claim 1, wherein R¹ is hydrogen, -F,    -Cl, C₁-C₈ alkyl, C₂-C₈ alkenyl, -CO₂H, -(C₀-C₄ alkyl)-C(O)O(C₁-C₆    alkyl), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (1c) hydrogen, -F, -Cl, C₁-C₆alkyl, C₂-C₆ alkenyl, -CO₂H, or-(C₀-C₂    alkyl)-C(O)O(C₁-C₆ alkyl);-   (1d) hydrogen;-   (1e) hydrogen, C₂-C₅ alkyl, or C₂-C₅ alkenyl;-   (1f) C₁-C₆ alkyl or C₂-C₆ alkenyl;-   (1g) C₁-C₆alkyl optionally substituted with hydroxy;-   (1h) C₁-C₆ alkyl, e.g. methyl, ethyl, or propyl (such as isopropyl    or n-propyl);-   (1i) C₂-C₆ alkenyl, e.g. isopropenyl;-   (1j) C₄-C₅ alkenyl, e.g., but-2-en-1-yl or 3-methylbut-2-en-1-yl;-   (1k) -CO₂H or -C(O)O(C₁-C₄ alkyl);(1l) -CO₂H;-   (1m) -CH₂OH;-   (1n) -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (1o) -OR^(1a), -(C₁-C₄ alkyl)OR^(1a), -SR^(1a), -(C₁-C₄    alkyl)SR^(1a), -NR^(1b)R^(1c), -(C₁-C₄ alkyl)NR^(1b)R^(1c), or    -(C₁-C₄ alkyl)C(O)NR^(1b)R^(1c);-   (1p) -OR^(1a), -(C₁-C₄ alkyl)OR^(1a), -NR^(1b)R^(1c), -(C₁-C₄    alkyl)NR^(1b)R^(1c), or -(C₁-C₄ alkyl)C(O)NR^(1b)R^(1c);-   (1q) as defined in (1o) and (1p), wherein R^(1a), R^(1b), and R^(1c)    are independently hydrogen or C₁-C₄ alkyl.

In certain embodiments of the compounds as otherwise described herein,R² is selected from one of the following groups (2a) - (2s):

-   (2a) hydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, -CO₂H, -(C₀-C₄    alkyl)-C(O)O(C₁-C₆ alkyl), -(C₁-C₄ alkyl)OR^(2a), -(C₁-C₄    alkyl)SR^(2a), -NR^(2b)R^(2c), -(C₁-C₄ alkyl)NR^(2b)R^(2c), -(C₁-C₄    alkyl)C(O)NR^(2b)R^(2C),-(C₀-C₄ alkyl)-aryl, -(C₀-C₄    alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, or -(C₀-C₄    alkyl)-heterocycloalkyl;-   (2b) hydrogen, -F, -Cl, C₁-C₈ alkyl, C₂-C₈ alkenyl, -CO₂H, -(C₁-C₄    alkyl)-OH, -(C₀-C₄ alkyl)-C(O)O(C₁-C₆ alkyl), -(C₀-C₄ alkyl)-aryl,    -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, or -(C₀-C₄    alkyl)-heterocycloalkyl;-   (2c) hydrogen, -F, -Cl, C₁-C₆ alkyl, C₂-C₆ alkenyl, -(C₁-C₂    alkyl)-OH, -CO₂H, or -(C₀-C₂ alkyl)-C(O)O(C₁-C₆ alkyl) (e.g.,    -CO₂(C₁-C₄ alkyl));-   (2d) hydrogen;-   (2e) C₁-C₄ alkyl or C₂-C₄ alkenyl;-   (2f) hydrogen, C₁-C₄ alkyl or C₂-C₄ alkenyl;-   (2g) C₁-C₄ alkyl optionally substituted with hydroxy;-   (2h) C₁-C₄ alkyl, e.g. methyl, ethyl, or propyl (such as isopropyl    or n-propyl);-   (2i) C₂-C₄ alkenyl, e.g. isopropenyl;-   (2j) -CO₂H or -C(O)O(C₁-C₄ alkyl);-   (2k) -CO₂H;-   (2l) -CH₂OH;-   (2m) -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (2n) -OR^(2a), -(C₁-C₄ alkyl)OR^(2a), -SR^(2a), -(C₁-C₄    alkyl)SR^(2a), -NR^(2b)R^(2c), -(C₁-C₄ alkyl)NR^(2b)R^(2c), or    -(C₁-C₄ alkyl)C(O)NR^(2b)R^(2c);-   (2o) -OR^(2a), -(C₁-C₄ alkyl)OR^(2a), -NR^(2b)R^(2c), -(C₁-C₄    alkyl)NR^(2b)R^(2c), or -(C₁-C₄ alkyl)C(O)NR^(2b)R^(2c);-   (2p) -OR^(2a);-   (2q) -NR^(2b)R^(2c);-   (2r) as defined in (2n) - (2q), wherein R^(2a), R^(2b), and R^(2c)    are independently hydrogen, C₁-C₄ alkyl, or -C(O)CH₃;-   (2s) as defined in (2n) - (2q), wherein R^(2a), R^(2b), and R^(2c)    are independently hydrogen or C₁-C₄ alkyl.

In certain embodiments of the compounds as otherwise described herein,R³ is selected from one of the following groups (3a) - (3p):

-   (3a) hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,    -(OCH₂CH₂)₀₋₆OCH₃, -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl,    -(C₀-C₄ alkyl)-cycloalkyl or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (3b) hydrogen, C₁-C₁₂ alkyl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (3c) hydrogen, C₁-C₈ alkyl, -(C₁-C₄ alkyl)-heteroaryl or -(C₁-C₄    alkyl)-heterocycloalkyl;-   (3d) hydrogen, C₄-C₉ alkyl, -(C₁-C₂ alkyl)-heteroaryl or -(C₁-C₂    alkyl)-heterocycloalkyl;-   (3e) hydrogen or C₁-C₁₀ alkyl;-   (3f) hydrogen;-   (3g) C₂-C₉ alkyl, e.g., unsubstituted n-C₂-C₉ alkyl;-   (3h) C₄-C₆ alkyl, e.g., unsubstituted n-C₄-C₆ alkyl;-   (3i) n-pentyl;-   (3j) 1,1-dimethylheptyl;-   (3k) n-propyl;-   (3l) -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (3m) -(C₀-C₄ alkyl)-heterocycloalkyl, wherein the heterocycloalkyl    has 3-8 ring members and 1-3 heteroatoms that are nitrogen, oxygen    or sulfur and is substituted with 0-4 R⁷;-   (3n) -(C₀-C₄ alkyl)-heterocycloalkyl, wherein the heterocycloalkyl    has 3-8 ring members and 1-3 heteroatoms that are nitrogen, oxygen    or sulfur and is substituted with 0-4 R⁷, wherein the    heterocycloalkyl is piperidinyl, pyrrolidinyl, azetidinyl, or    aziridinyl;-   (3o) -(C₀-C₄ alkyl)-heterocycloalkyl, wherein the heterocycloalkyl    has 3-8 ring members and 1-3 heteroatoms that are nitrogen, oxygen    or sulfur and is substituted with 0-4 R⁷, wherein the    heterocycloalkyl is azetidinyl and is substituted with 1-2 R⁷ which    are independently oxo, C₁-C₄ alkyl, Cl, F, Br, -C(O)R^(A),    or-CO₂R^(A), wherein R^(A) is H or C₁-C₃ alkyl;-   (3p) -(C₀-C₄ alkyl)-heterocycloalkyl, wherein the heterocycloalkyl    has 3-8 ring members and 1-3 heteroatoms that are nitrogen, oxygen    or sulfur and is substituted with 0-4 R⁷, wherein R⁷ is -C(O)CH₃.

In certain embodiments of the compounds as otherwise described herein,R⁵ are independently selected from one of the following groups (4a) -(4c):

-   (4a) hydrogen, C₁-C₆ alkyl, -(C₁-C₄ alkyl)-O-(C₁-C₄ alkyl),    -C(O)(C₁-C₄ alkyl), -C(O)O(C₁-C₄ alkyl), -C(O)NH₂, -C(O)NH(C₁-C₄    alkyl), or -C(O)N(C₁-C₄ alkyl)₂;-   (4b) hydrogen, C₁-C₆ alkyl, or -(C₁-C₄ alkyl)-O-(C₁-C₄ alkyl);-   (4c) hydrogen.

In certain embodiments of the compounds as otherwise described herein,R⁶ are independently selected from one of the following groups (5a) -(5e)

-   (5a) hydrogen;-   (5b) -OR^(6a);-   (5c) -OR^(6a), wherein R^(6a) is hydrogen, C₁-C₆ alkyl, -(C₁-C₄    alkyl)-O-(C₁-C₄ alkyl), -C(O)(C₁-C₄ alkyl), -C(O)O(C₁-C₄ alkyl),    -C(O)NH₂, -C(O)NH(C₁-C₄ alkyl), or -C(O)N(C₁-C₄ alkyl)₂;-   (5d) -OR^(6a), wherein R^(6a) is hydrogen, C₁-C₆ alkyl, or -(C₁-C₄    alkyl)-O-(C₁-C₄ alkyl);-   (5e) -OH.

In certain embodiments of the compounds as otherwise described herein,the compound has the structural formulae (la)-(le):

In certain embodiments of the compounds as otherwise described herein,R⁴ is selected from one of the following groups (6a) - (6e):

or

(6e) sulfo, methylsulfonyl, cyclopropylsulfonyl, tert-butylsulfonyl,benzylsulfonyl, phenylsulfonyl, (4-nitrophenyl)sulfonyl,pyridin-3-ylsulfonyl, furan-2-ylsulfonyl, (1H-imidazol-4-yl)sulfonyl,oxetan-3-ylsulfonyl, perfluorophenylsulfonyl, (4-oxocyclohexyl)sulfonyl,(2-(2,5-dioxopyrrolidin-1-yl)ethyl)sulfonyl,(2-(dimethylamino)ethyl)sulfonyl, (1-acetylpiperidin-3-yl)sulfonyl,(2-chloropyrimidin-5-yl)sulfonyl, sulfamoyl, N-methylsulfamoyl,N,N-dimethylsulfamoyl, N-cyclopropylsulfamoyl, N-isopropylsulfamoyl,N-phenylsulfamoyl, N-benzylsulfamoyl, (4-methylpiperazin-1-yl)sulfonyl,piperidin-1-ylsulfonyl, morpholinosulfonyl, N-(pyridin-3-yl)sulfamoyl,N-(pyrimidin-2-yl)sulfamoyl, N-(2-oxopropyl)sulfamoyl,(3-oxoazetidin-1-yl)sulfonyl, N-(oxetan-2-ylmethyl)sulfamoyl,(2-azaspiro[3.3]heptan-2-yl)sulfonyl,(2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl, N-(1-carboxyethyl)sulfamoyl,N-(1-methoxy-1-oxopropan-2-yl)sulfamoyl,N-(3-morpholinopropanoyl)sulfamoyl, N-(3-carboxypropanoyl)sulfamoyl,N-(3-(4-methylpiperazin-1-yl)propanoyl)sulfamoyl, N-glycylsulfamoyl,N-(2-(2-methoxyethoxy)acetyl)sulfamoyl, N-serylsulfamoyl,N-alanylsulfamoyl, (3-amino-2-methylpropanoyl)sulfamoyl,N-acetylsulfamoyl, N-(3-oxobutanoyl)sulfamoyl,N-(2-(3-methyl-1H-1,2,4-triazol-5-yl)acetyl)sulfamoyl,N-(1H-1,2,4-triazole-5-carbonyl)sulfamoyl,N-(cyclobutanecarbonyl)sulfamoyl, N-benzoylsulfamoyl,N-nicotinoylsulfamoyl, N-(2-phenylacetyl)sulfamoyl,N-(2-(furan-2-yl)acetyl)sulfamoyl, N-(2-(oxazol-2-yl)acetyl)sulfamoyl,N-(2-(thiazol-2-yl)acetyl)sulfamoyl,N-(2-(1H-benzo[d]imidazole-2-yl)acetyl)sulfamoyl,(phenylsulfonyl)carbamoyl, (cyclohexylsulfonyl)carbamoyl,(prop-1-en-1-ylsulfonyl)carbamoyl, ((1H-benzo[d]imidazol-2-yl)sulfonyl)carbamoyl.

In certain embodiments of the compounds as otherwise described herein,R^(4a), R^(4b), or R^(4c) is selected from one of the following groups(7a) - (7gg) as appropriate:

-   (7a) as defined in (6a) - (6c), wherein R^(4a) is C₁-C₈ alkyl, C₂-C₈    alkenyl, -OR^(4e), -(C₁-C₄ alkyl)OR^(4e), -(C₁-C₄ alkyl)-C(O)(C₁-C₄    alkyl), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl, -(C₀-C₄ alkyl)-heterocycloalkyl, -NR^(4d)R^(4e),    or -(C₁-C₄ alkyl)NR^(4d)R^(4e);-   (7b) as defined in (6a) - (6c), wherein R^(4a) is C₁-C₈ alkyl, C₂-C₈    alkenyl, or -OR^(4e);-   (7c) as defined in (6a) - (6c), wherein R^(4a) is C₂-C₆ alkenyl    (e.g., propenyl or 3-methoxyprop-1-en-1-yl);-   (7d) as defined in (6a) - (6c), wherein R^(4a) is C₁-C₄ alkyl (e.g.,    methyl or tert-butyl);-   (7e) as defined in (6a) - (6c), wherein R^(4a) is -OR^(4e) (e.g.,    -OH or -ONa);-   (7f) as defined in (6a) - (6c), wherein R^(4a) is C₁-C₈ alkyl, C₂-C₈    alkenyl, -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄    alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (7g) as defined in (6a) - (6c), wherein R^(4a) is -(C₀-C₄    alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl,    or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (7h) as defined in (6a) - (6c), wherein R^(4a) is monocyclic -(C₀-C₁    alkyl)-aryl (e.g., phenyl or benzyl), monocyclic or bicyclic -(C₀-C₁    alkyl)-heteroaryl (e.g., pyridiyl, triazolyl, oxazolyl, furanyl,    imidazolyl, pyrimidinyl. or benzimidazolyl), monocyclic -(C₀-C₁    alkyl)-cycloalkyl. (e.g. cyclopropyl, cyclopropanyl or cyclohexyl)    or monocyclic -(C₀-C₂ alkyl)-heterocycloalkyl (e.g., oxetanylmethyl,    azetidinyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,    oxetanyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl);-   (7i) as defined in (6a) - (6c), wherein R^(4a) is monocyclic -(C₀-C₁    alkyl)-aryl (e.g., phenyl or benzyl) or monocyclic -(C₀-C₁    alkyl)-cycloalkyl. (e.g. cyclopropyl, cyclopropanyl or cyclohexyl);-   (7j) as defined in (6a) - (6c), wherein R^(4a) is monocyclic or    bicyclic -(C₀-C₁ alkyl)-heteroaryl (e.g., pyridiyl, triazolyl,    oxazolyl, furanyl, imidazolyl, pyrimidinyl. or benzimidazolyl) or    monocyclic -(C₀-C₂ alkyl)-heterocycloalkyl (e.g., oxetanylmethyl,    azetidinyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,    oxetanyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl);-   (7k) as defined in (7h) - (7j), wherein R⁸ is independently C₁-C₄    alkyl, -F, -Cl, nitro, amino, methoxymethyl, cyclopropyl, phenyl,    pyridyl, or -NR^(B)C(O)R^(A), wherein R^(B) is hydrogen or methyl    and R^(A) is hydrogen or C₁-C₄ alkyl;-   (7I) as defined in (7h) - (7k), wherein each R⁷ is independently    C₁-C₄ alkyl, methoxymethyl, -F, -Cl, hydroxy, oxo, cyclopropyl,    phenyl, or pyridyl;-   (7m) as defined in (6a) - (6c), wherein R^(4a) is -(C₁-C₄    alkyl)NR^(4d)R^(4e) (e.g., wherein R^(4d) and R^(4e) are    independently H or C₁-C₄ alkyl, such as (dimethylamino)ethyl,    aminopropan-2-yl, aminoethyl or 1-amino-2-hydroxyethyl);-   (7n) as defined in (6a) - (6c), wherein R^(4a) is -NR^(4d)R^(4e);-   (7o) as defined in (6a) - (6c), wherein R^(4a) is NR^(4d)R^(4e),    wherein R^(4d) is hydrogen, C₁-C₄ alkyl, -(C₁-C₄    alkyl)-C(O)O(R^(4e)), -(C₀-C₂ alkyl)-aryl, -(C₀-C₂    alkyl)-heteroaryl, -(C₀-C₂ alkyl)-cycloalkyl, or -(C₀-C₂    alkyl)-heterocycloalkyl and R^(4e) is hydrogen or C₁-C₄ alkyl;-   (7p) as defined in (6a) - (6c), wherein R^(4a) is -NR^(4d)R^(4e),    wherein R^(4d) is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl and R^(4e)    is hydrogen or methyl;-   (7q) as defined in (6a) - (6c), wherein R^(4a) is -NR^(4d)R^(4e),    wherein R^(4d) is -(C₀-C₁ alkyl)-aryl, -(C₀-C₁ alkyl)-heteroaryl,    -(C₀-C₁ alkyl)-cycloalkyl, or -(C₀-C₁ alkyl)-heterocycloalkyl and    R^(4e) is hydrogen or methyl;-   (7r) as defined in (6b) or (6d), wherein R^(4b) is C₁-C₈ alkyl,    C₂-C₈ alkenyl, -CH₂-(OCH₂CH₂)₀₋₆O(C₁-C₆ alkyl), -(C₁-C₄    alkyl)-C(O)O(R^(4e)), -(C₁-C₄ alkyl)OR^(4e), -(C₁-C₄    alkyl)-C(O)(C₁-C₄ alkyl), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄    alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, -(C₀-C₄    alkyl)-heterocycloalkyl, or -(C₁-C₄ alkyl)NR^(4d)R^(4e);-   (7s) as defined in (6b) or (6d), wherein R^(4b) is C₁-C₈ alkyl,    C₂-C₈ alkenyl, or -(C₁-C₄ alkyl)OR^(4e);-   (7t) as defined in (6b) or (6d), wherein R^(4b) is C₁-C₄ alkyl,    e.g., methyl;-   (7u) as defined in (6b) or (6d), wherein R^(4b) is    -CH₂-(OCH₂CH₂)₀₋₄O(C₁-C₆ alkyl), -(C₁-C₄ alkyl)-C(O)O(R^(4e)) (e.g.,    -(C₁-C₄ alkyl)-C(O)OH), or -(C₁-C₄ alkyl)-C(O)(C₁-C₄ alkyl) (e.g.,    -CH₂C(O)CH₃);-   (7v) as defined in (6b) or (6d), wherein R^(4b) is C₁-C₈ alkyl,    C₂-C₈ alkenyl, -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl,    -(C₀-C₄ alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (7w) as defined in (6b) or (6d), wherein R^(4b) is -(C₀-C₄    alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl,    or -(C₀-C₄ alkyl)-heterocycloalkyl;-   (7x) as defined in (6b) or (6d), wherein R^(4b) monocyclic -(C₀-C₁    alkyl)-aryl (e.g., phenyl or benzyl), monocyclic or bicyclic -(C₀-C₁    alkyl)-heteroaryl (e.g., pyridiyl, triazolyl, oxazolyl, furanyl,    imidazolyl, pyrimidinyl. or benzimidazolyl), monocyclic -(C₀-C₁    alkyl)-cycloalkyl. (e.g. cyclopropyl, cyclopropanyl or cyclohexyl)    or monocyclic -(C₀-C₂ alkyl)-heterocycloalkyl (e.g., oxetanylmethyl,    azetidinyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,    oxetanyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl);-   (7y) as defined in (6b) or (6d), wherein R^(4b) is monocyclic    -(C₀-C₁ alkyl)-aryl (e.g., phenyl or benzyl) or monocyclic -(C₀-C₁    alkyl)-cycloalkyl. (e.g. cyclopropyl, cyclopropanyl or cyclohexyl);-   (7z) as defined in (6b) or (6d), wherein R^(4b) is monocyclic or    bicyclic -(C₀-C₁ alkyl)-heteroaryl (e.g., pyridiyl, triazolyl,    oxazolyl, furanyl, imidazolyl, pyrimidinyl. or benzimidazolyl) or    monocyclic -(C₀-C₂ alkyl)-heterocycloalkyl (e.g., oxetanylmethyl,    azetidinyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,    oxetanyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl);-   (7aa) as defined in (7v) - (7z), wherein each R⁸ is independently    C₁-C₄ alkyl, -F, -Cl, nitro, amino, methoxymethyl, cyclopropyl,    phenyl, pyridyl, or -NR^(B)C(O)R^(A), wherein R^(B) is hydrogen or    methyl and R^(A) is hydrogen or C₁-C₄ alkyl;-   (7bb) as defined in (7v) - (7aa), wherein each R⁷ is independently    C₁-C₄ alkyl, methoxymethyl, -F, -Cl, hydroxy, oxo, cyclopropyl,    phenyl, or pyridyl;-   (7cc) as defined in (6b) or (6d), wherein R^(4b) is -(C₁-C₄    alkyl)NR^(4d)R^(4e) (e.g., wherein R^(4d) and R^(4e) are    independently H or C₁-C₄ alkyl, such as (dimethylamino)ethyl,    aminopropan-2-yl, aminoethyl or 1-amino-2-hydroxyethyl);-   (7dd) as defined in (6b) - (6d) or (7a) - (7y), wherein R^(4c) is    hydrogen;-   (7ee) as defined in (6b) - (6d) or (7a) - (7y), wherein R^(4c) is    C₁-C₄ alkyl, e.g., methyl.-   (7ff) as defined in (7a), (7m), (7r),or (7cc), wherein R^(4d) is    hydrogen or C₁-C₆ alkyl (e.g., methyl, ethyl, or propyl).-   (7gg) as defined in (7a), (7m), (7r),or (7cc), wherein R^(4e) is    hydrogen, methyl, or aryl.

Various particular embodiment nos. 1-477 of compounds of the presentdisclosure include compounds of formula (I), each as defined in each ofthe following rows (or enantiomers, diastereomers, racemates, tautomers,or metabolites thereof, or pharmaceutically acceptable salts, solvatesor hydrates of the compounds, enantiomers, diastereomers, racemates,tautomers, or metabolites), wherein each entry is a group number asdefined above:

Embodiment R¹ R² R³ R⁵ R⁶ R⁴ R^(4a) R^(4b) R^(4c) 1 (1d) (2c) (3a) (4b)(5d) (6a) (7a) - - 2 (1d) (2c) (3a) (4b) (5d) (6a) (7b),(7g) - - 3 (1d)(2c) (3a) (4b) (5d) (6c) (7a) - (7dd) 4 (1d) (2c) (3a) (4b) (5d) (6c)(7b),(7g) - (7dd) 5 (1d) (2c) (3a) (4b) (5d) (6d) - (7r) (7dd) 6 (1d)(2c) (3a) (4b) (5d) (6d) - (7s),(7w) (7dd) 7 (1d) (2c) (3a) (4b) (5e)(6a) (7a) - - 8 (1d) (2c) (3a) (4b) (5e) (6a) (7b),(7g) - - 9 (1d) (2c)(3a) (4b) (5e) (6c) (7a) - (7dd) 10 (1d) (2c) (3a) (4b) (5e) (6c)(7b),(7g) - (7dd) 11 (1d) (2c) (3a) (4b) (5e) (6d) - (7r) (7dd) 12 (1d)(2c) (3a) (4b) (5e) (6d) - (7s),(7w) (7dd) 13 (1d) (2c) (3a) (4c) (5d)(6a) (7a) - - 14 (1d) (2c) (3a) (4c) (5d) (6a) (7b),(7g) - - 15 (1d)(2c) (3a) (4c) (5d) (6c) (7a) - (7dd) 16 (1d) (2c) (3a) (4c) (5d) (6c)(7b),(7g) - (7dd) 17 (1d) (2c) (3a) (4c) (5d) (6d) - (7r) (7dd) 18 (1d)(2c) (3a) (4c) (5d) (6d) - (7s),(7w) (7dd) 19 (1d) (2c) (3a) (4c) (5e)(6a) (7a) - - 20 (1d) (2c) (3a) (4c) (5e) (6a) (7b),(7g) - - 21 (1d)(2c) (3a) (4c) (5e) (6c) (7a) - (7dd) 22 (1d) (2c) (3a) (4c) (5e) (6c)(7b),(7g) - (7dd) 23 (1d) (2c) (3a) (4c) (5e) (6d) - (7r) (7dd) 24 (1d)(2c) (3a) (4c) (5e) (6d) - (7s),(7w) (7dd) 25 (1d) (2c) (3d) (4b) (5d)(6a) (7a) - - 26 (1d) (2c) (3d) (4b) (5d) (6a) (7b),(7g) - - 27 (1d)(2c) (3d) (4b) (5d) (6c) (7a) - (7dd) 28 (1d) (2c) (3d) (4b) (5d) (6c)(7b),(7g) - (7dd) 29 (1d) (2c) (3d) (4b) (5d) (6d) - (7r) (7dd) 30 (1d)(2c) (3d) (4b) (5d) (6d) - (7s),(7w) (7dd) 31 (1d) (2c) (3d) (4b) (5e)(6a) (7a) - - 32 (1d) (2c) (3d) (4b) (5e) (6a) (7b),(7g) - - 33 (1d)(2c) (3d) (4b) (5e) (6c) (7a) - (7dd) 34 (1d) (2c) (3d) (4b) (5e) (6c)(7b),(7g) (7dd) 35 (1d) (2c) (3d) (4b) (5e) (6d) - (7r) (7dd) 36 (1d)(2c) (3d) (4b) (5e) (6d) - (7s),(7w) (7dd) 37 (1d) (2c) (3d) (4c) (5d)(6a) (7a) - - 38 (1d) (2c) (3d) (4c) (5d) (6a) (7b),(7g) - - 39 (1d)(2c) (3d) (4c) (5d) (6c) (7a) - (7dd) 40 (1d) (2c) (3d) (4c) (5d) (6c)(7b),(7g) - (7dd) 41 (1d) (2c) (3d) (4c) (5d) (6d) - (7r) (7dd) 42 (1d)(2c) (3d) (4c) (5d) (6d) - (7s),(7w) (7dd) 43 (1d) (2c) (3d) (4c) (5e)(6a) (7a) - - 44 (1d) (2c) (3d) (4c) (5e) (6a) (7b),(7g) - - 45 (1d)(2c) (3d) (4c) (5e) (6c) (7a) - (7dd) 46 (1d) (2c) (3d) (4c) (5e) (6c)(7b),(7g) - (7dd) 47 (1d) (2c) (3d) (4c) (5e) (6d) - (7r) (7dd) 48 (1d)(2c) (3d) (4c) (5e) (6d) - (7s),(7w) (7dd) 49 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7a) - - 50 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7b),(7g) - - 51 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7a) - (7dd) 52 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7b),(7g) - (7dd) 53 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7r) (7dd) 54 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7s),(7w) (7dd) 55 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7a) - - 56 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7b),(7g) - - 57 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7a) - (7dd) 58 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7b),(7g) - (7dd) 59 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7r) (7dd) 60 (1d) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7s),(7w) (7dd) 61 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7a) - - 62 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7b),(7g) - - 63 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7a) - (7dd) 64 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7b),(7g) - (7dd) 65 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7r) (7dd) 66 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7s),(7w) (7dd) 67 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7a) - - 68 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7b),(7g) - - 69 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7a) - (7dd) 70 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7b),(7g) - (7dd) 71 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7r) (7dd) 72 (1d) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7s),(7w) (7dd) 73 (1d) (2g) (3a)(4b) (5d) (6a) (7a) - - 74 (1d) (2g) (3a) (4b) (5d) (6a) (7b),(7g) - -75 (1d) (2g) (3a) (4b) (5d) (6c) (7a) - (7dd) 76 (1d) (2g) (3a) (4b)(5d) (6c) (7b),(7g) - (7dd) 77 (1d) (2g) (3a) (4b) (5d) (6d) - (7r)(7dd) 78 (1d) (2g) (3a) (4b) (5d) (6d) - (7s),(7w) (7dd) 79 (1d) (2g)(3a) (4b) (5e) (6a) (7a) - - 80 (1d) (2g) (3a) (4b) (5e) (6a)(7b),(7g) - - 81 (1d) (2g) (3a) (4b) (5e) (6c) (7a) - (7dd) 82 (1d) (2g)(3a) (4b) (5e) (6c) (7b),7g) - (7dd) 83 (1d) (2g) (3a) (4b) (5e) (6d) -(7r) (7dd) 84 (1d) (2g) (3a) (4b) (5e) (6d) - (7s),(7w) (7dd) 85 (1d)(2g) (3a) (4c) (5d) (6a) (7a) - - 86 (1d) (2g) (3a) (4c) (5d) (6a)(7b),(7g) - - 87 (1d) (2g) (3a) (4c) (5d) (6c) (7a) - (7dd) 88 (1d) (2g)(3a) (4c) (5d) (6c) (7b),(7g) - (7dd) 89 (1d) (2g) (3a) (4c) (5d) (6d) -(7r) (7dd) 90 (1d) (2g) (3a) (4c) (5d) (6d) - (7s),(7w) (7dd) 91 (1d)(2g) (3a) (4c) (5e) (6a) (7a) - - 92 (1d) (2g) (3a) (4c) (5e) (6a)(7b),(7g) - - 93 (1d) (2g) (3a) (4c) (5e) (6c) (7a) - (7dd) 94 (1d) (2g)(3a) (4c) (5e) (6c) (7b),(7g) - (7dd) 95 (1d) (2g) (3a) (4c) (5e) (6d) -(7r) (7dd) 96 (1d) (2g) (3a) (4c) (5e) (6d) - (7s),(7w) (7dd) 97 (1d)(2g) (3d) (4b) (5d) (6a) (7a) - - 98 (1d) (2g) (3d) (4b) (5d) (6a)(7b),(7g) - - 99 (1d) (2g) (3d) (4b) (5d) (6c) (7a) - (7dd) 100 (1d)(2g) (3d) (4b) (5d) (6c) (7b),(7g) - (7dd) 101 (1d) (2g) (3d) (4b) (5d)(6d) - (7r) (7dd) 102 (1d) (2g) (3d) (4b) (5d) (6d) - (7s),(7w) (7dd)103 (1d) (2g) (3d) (4b) (5e) (6a) (7a) - - 104 (1d) (2g) (3d) (4b) (5e)(6a) (7b),(7g) - - 105 (1d) (2g) (3d) (4b) (5e) (6c) (7a) - (7dd) 106(1d) (2g) (3d) (4b) (5e) (6c) (7b),(7g) - (7dd) 107 (1d) (2g) (3d) (4b)(5e) (6d) - (7r) (7dd) 108 (1d) (2g) (3d) (4b) (5e) (6d) - (7s),(7w)(7dd) 109 (1d) (2g) (3d) (4c) (5d) (6a) (7a) - - 110 (1d) (2g) (3d) (4c)(5d) (6a) (7b),(7g) - - 111 (1d) (2g) (3d) (4c) (5d) (6c) (7a) - (7dd)112 (1d) (2g) (3d) (4c) (5d) (6c) (7b),(7g) - (7dd) 113 (1d) (2g) (3d)(4c) (5d) (6d) - (7r) (7dd) 114 (1d) (2g) (3d) (4c) (5d) (6d) -(7s),(7w) (7dd) 115 (1d) (2g) (3d) (4c) (5e) (6a) (7a) - - 116 (1d) (2g)(3d) (4c) (5e) (6a) (7b),(7g) - - 117 (1d) (2g) (3d) (4c) (5e) (6c)(7a) - (7dd) 118 (1d) (2g) (3d) (4c) (5e) (6c) (7b),(7g) - (7dd) 119(1d) (2g) (3d) (4c) (5e) (6d) - (7r) (7dd) 120 (1d) (2g) (3d) (4c) (5e)(6d) - (7s),(7w) (7dd) 121 (1d) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6a)(7a) - - 122 (1d) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6a) (7b),(7g) - -123 (1d) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6c) (7a) - (7dd) 124 (1d)(2g) (3g),(3i),(3j),(3k) (4b) (5d) (6c) (7b),(7g) - (7dd) 125 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7r) (7dd) 126 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7s),(7w) (7dd) 127 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7a) - - 128 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7b),(7g) - - 129 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7a) - (7dd) 130 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7b),(7g) - (7dd) 131 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7r) (7dd) 132 (1d) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7s),(7w) (7dd) 133 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7a) - - 134 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7b),(7g) - - 135 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7a) - (7dd) 136 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7b),(7g) - (7dd) 137 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7r) (7dd) 138 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7s),(7w) (7dd) 139 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7a) - - 140 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7b),(7g) - - 141 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7a) - (7dd) 142 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7b),(7g) - (7dd) 143 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7r) (7dd) 144 (1d) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7s),(7w) (7dd) 145 (1e) (2c) (3a)(4b) (5d) (6a) (7a) - - 146 (1e) (2c) (3a) (4b) (5d) (6a) (7b),(7g) - -147 (1e) (2c) (3a) (4b) (5d) (6c) (7a) - (7dd) 148 (1e) (2c) (3a) (4b)(5d) (6c) (7b),(7g) - (7dd) 149 (1e) (2c) (3a) (4b) (5d) (6d) - (7r)(7dd) 150 (1e) (2c) (3a) (4b) (5d) (6d) - (7s),(7w) (7dd) 151 (1e) (2c)(3a) (4b) (5e) (6a) (7a) - - 152 (1e) (2c) (3a) (4b) (5e) (6a)(7b),(7g) - - 153 (1e) (2c) (3a) (4b) (5e) (6c) (7a) - (7dd) 154 (1e)(2c) (3a) (4b) (5e) (6c) (7b),(7g) - (7dd) 155 (1e) (2c) (3a) (4b) (5e)(6d) - (7r) (7dd) 156 (1e) (2c) (3a) (4b) (5e) (6d) - (7s),(7w) (7dd)157 (1e) (2c) (3a) (4c) (5d) (6a) (7a) - - 158 (1e) (2c) (3a) (4c) (5d)(6a) (7b),(7g) - - 159 (1e) (2c) (3a) (4c) (5d) (6c) (7a) - (7dd) 160(1e) (2c) (3a) (4c) (5d) (6c) (7b),(7g) - (7dd) 161 (1e) (2c) (3a) (4c)(5d) (6d) - (7r) (7dd) 162 (1e) (2c) (3a) (4c) (5d) (6d) - (7s),(7w)(7dd) 163 (1e) (2c) (3a) (4c) (5e) (6a) (7a) - - 164 (1e) (2c) (3a) (4c)(5e) (6a) (7b),(7g) - - 165 (1e) (2c) (3a) (4c) (5e) (6c) (7a) - (7dd)166 (1e) (2c) (3a) (4c) (5e) (6c) (7b),(7g) - (7dd) 167 (1e) (2c) (3a)(4c) (5e) (6d) - (7r) (7dd) 168 (1e) (2c) (3a) (4c) (5e) (6d) -(7s),(7w) (7dd) 169 (1e) (2c) (3d) (4b) (5d) (6a) (7a) - - 170 (1e) (2c)(3d) (4b) (5d) (6a) (7b),(7g) - - 171 (1e) (2c) (3d) (4b) (5d) (6c)(7a) - (7dd) 172 (1e) (2c) (3d) (4b) (5d) (6c) (7b),(7g) - (7dd) 173(1e) (2c) (3d) (4b) (5d) (6d) - (7r) (7dd) 174 (1e) (2c) (3d) (4b) (5d)(6d) - (7s),(7w) (7dd) 175 (1e) (2c) (3d) (4b) (5e) (6a) (7a) - - 176(1e) (2c) (3d) (4b) (5e) (6a) (7b),(7g) - - 177 (1e) (2c) (3d) (4b) (5e)(6c) (7a) - (7dd) 178 (1e) (2c) (3d) (4b) (5e) (6c) (7b),(7g) - (7dd)179 (1e) (2c) (3d) (4b) (5e) (6d) - (7r) (7dd) 180 (1e) (2c) (3d) (4b)(5e) (6d) - (7s),(7w) (7dd) 181 (1e) (2c) (3d) (4c) (5d) (6a) (7a) - -182 (1e) (2c) (3d) (4c) (5d) (6a) (7b),(7g) - - 183 (1e) (2c) (3d) (4c)(5d) (6c) (7a) - (7dd) 184 (1e) (2c) (3d) (4c) (5d) (6c) (7b),(7g) -(7dd) 185 (1e) (2c) (3d) (4c) (5d) (6d) - (7r) (7dd) 186 (1e) (2c) (3d)(4c) (5d) (6d) - (7s),(7w) (7dd) 187 (1e) (2c) (3d) (4c) (5e) (6a)(7a) - - 188 (1e) (2c) (3d) (4c) (5e) (6a) (7b),(7g) - - 189 (1e) (2c)(3d) (4c) (5e) (6c) (7a) - (7dd) 190 (1e) (2c) (3d) (4c) (5e) (6c)(7b),(7g) - (7dd) 191 (1e) (2c) (3d) (4c) (5e) (6d) - (7r) (7dd) 192(1e) (2c) (3d) (4c) (5e) (6d) - (7s),(7w) (7dd) 193 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7a) - - 194 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7b),(7g) - - 195 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7a) - (7dd) 196 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7b),(7g) - (7dd) 197 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7r) (7dd) 198 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7s),(7w) (7dd) 199 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7a) - - 200 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7b),(7g) - - 201 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7a) - (7dd) 202 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7b),(7g) - (7dd) 203 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7r) (7dd) 204 (1e) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7s),(7w) (7dd) 205 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7a) - - 206 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7b),(7g) - - 207 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7a) - (7dd) 208 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7b),(7g) - (7dd) 209 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7r) (7dd) 210 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7s),(7w) (7dd) 211 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7a) - - 212 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7b),(7g) - - 213 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7a) - (7dd) 214 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7b),(7g) - (7dd) 215 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7r) (7dd) 216 (1e) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7s),(7w) (7dd) 217 (1e) (2g) (3a)(4b) (5d) (6a) (7a) - - 218 (1e) (2g) (3a) (4b) (5d) (6a) (7b),(7g) - -219 (1e) (2g) (3a) (4b) (5d) (6c) (7a) - (7dd) 220 (1e) (2g) (3a) (4b)(5d) (6c) (7b),(7g) - (7dd) 221 (1e) (2g) (3a) (4b) (5d) (6d) - (7r)(7dd) 222 (1e) (2g) (3a) (4b) (5d) (6d) - (7s),(7w) (7dd) 223 (1e) (2g)(3a) (4b) (5e) (6a) (7a) - - 224 (1e) (2g) (3a) (4b) (5e) (6a)(7b),(7g) - - 225 (1e) (2g) (3a) (4b) (5e) (6c) (7a) - (7dd) 226 (1e)(2g) (3a) (4b) (5e) (6c) (7b),(7g) - (7dd) 227 (1e) (2g) (3a) (4b) (5e)(6d) - (7r) (7dd) 228 (1e) (2g) (3a) (4b) (5e) (6d) - (7s),(7w) (7dd)229 (1e) (2g) (3a) (4c) (5d) (6a) (7a) - - 230 (1e) (2g) (3a) (4c) (5d)(6a) (7b),(7g) - - 231 (1e) (2g) (3a) (4c) (5d) (6c) (7a) - (7dd) 232(1e) (2g) (3a) (4c) (5d) (6c) (7b),(7g) - (7dd) 233 (1e) (2g) (3a) (4c)(5d) (6d) - (7r) (7dd) 234 (1e) (2g) (3a) (4c) (5d) (6d) - (7s),(7w)(7dd) 235 (1e) (2g) (3a) (4c) (5e) (6a) (7a) - - 236 (1e) (2g) (3a) (4c)(5e) (6a) (7b),(7g) - - 237 (1e) (2g) (3a) (4c) (5e) (6c) (7a) - (7dd)238 (1e) (2g) (3a) (4c) (5e) (6c) (7b),(7g) - (7dd) 239 (1e) (2g) (3a)(4c) (5e) (6d) - (7r) (7dd) 240 (1e) (2g) (3a) (4c) (5e) (6d) -(7s),(7w) (7dd) 241 (1e) (2g) (3d) (4b) (5d) (6a) (7a) - - 242 (1e) (2g)(3d) (4b) (5d) (6a) (7b),(7g) - - 243 (1e) (2g) (3d) (4b) (5d) (6c)(7a) - (7dd) 244 (1e) (2g) (3d) (4b) (5d) (6c) (7b),(7g) - (7dd) 245(1e) (2g) (3d) (4b) (5d) (6d) - (7r) (7dd) 246 (1e) (2g) (3d) (4b) (5d)(6d) - (7s),(7w) (7dd) 247 (1e) (2g) (3d) (4b) (5e) (6a) (7a) - - 248(1e) (2g) (3d) (4b) (5e) (6a) (7b),(7g) - - 249 (1e) (2g) (3d) (4b) (5e)(6c) (7a) - (7dd) 250 (1e) (2g) (3d) (4b) (5e) (6c) (7b),(7g) - (7dd)251 (1e) (2g) (3d) (4b) (5e) (6d) - (7r) (7dd) 252 (1e) (2g) (3d) (4b)(5e) (6d) - (7s),(7w) (7dd) 253 (1e) (2g) (3d) (4c) (5d) (6a) (7a) - -254 (1e) (2g) (3d) (4c) (5d) (6a) (7b),(7g) - - 255 (1e) (2g) (3d) (4c)(5d) (6c) (7a) - (7dd) 256 (1e) (2g) (3d) (4c) (5d) (6c) (7b),(7g) -(7dd) 257 (1e) (2g) (3d) (4c) (5d) (6d) - (7r) (7dd) 258 (1e) (2g) (3d)(4c) (5d) (6d) - (7s),(7w) (7dd) 259 (1e) (2g) (3d) (4c) (5e) (6a)(7a) - - 260 (1e) (2g) (3d) (4c) (5e) (6a) (7b),(7g) - - 261 (1e) (2g)(3d) (4c) (5e) (6c) (7a) - (7dd) 262 (1e) (2g) (3d) (4c) (5e) (6c)(7b),(7g) - (7dd) 263 (1e) (2g) (3d) (4c) (5e) (6d) - (7r) (7dd) 264(1e) (2g) (3d) (4c) (5e) (6d) - (7s),(7w) (7dd) 265 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7a) - - 266 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7b),(7g) - - 267 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7a) - (7dd) 268 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7b),(7g) - (7dd) 269 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7r) (7dd) 270 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7s),(7w) (7dd) 271 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7a) - - 272 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7b),(7g) - - 273 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7a) - (7dd) 274 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7b),(7g) - (7dd) 275 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7r) (7dd) 276 (1e) (2g)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7s),(7w) (7dd) 277 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7a) - - 278 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7b),(7g) - - 279 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7a) - (7dd) 280 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7b),(7g) - (7dd) 281 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7r) (7dd) 282 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7s),(7w) (7dd) 283 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7a) - - 284 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7b),(7g) - - 285 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7a) - (7dd) 286 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7b),(7g) - (7dd) 287 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7r) (7dd) 288 (1e) (2g)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7s),(7w) (7dd) 289 (1i) (2c) (3a)(4b) (5d) (6a) (7a) - - 290 (1i) (2c) (3a) (4b) (5d) (6a) (7b),(7g) - -291 (1i) (2c) (3a) (4b) (5d) (6c) (7a) - (7dd) 292 (1i) (2c) (3a) (4b)(5d) (6c) (7b),(7g) - (7dd) 293 (1i) (2c) (3a) (4b) (5d) (6d) - (7r)(7dd) 294 (1i) (2c) (3a) (4b) (5d) (6d) - (7s),(7w) (7dd) 295 (1i) (2c)(3a) (4b) (5e) (6a) (7a) - - 296 (1i) (2c) (3a) (4b) (5e) (6a)(7b),(7g) - - 297 (1i) (2c) (3a) (4b) (5e) (6c) (7a) - (7dd) 298 (1i)(2c) (3a) (4b) (5e) (6c) (7b),(7g) - (7dd) 299 (1i) (2c) (3a) (4b) (5e)(6d) - (7r) (7dd) 300 (1i) (2c) (3a) (4b) (5e) (6d) - (7s),(7w) (7dd)301 (1i) (2c) (3a) (4c) (5d) (6a) (7a) - - 302 (1i) (2c) (3a) (4c) (5d)(6a) (7b),(7g) - - 303 (1i) (2c) (3a) (4c) (5d) (6c) (7a) - (7dd) 304(1i) (2c) (3a) (4c) (5d) (6c) (7b),(7g) - (7dd) 305 (1i) (2c) (3a) (4c)(5d) (6d) - (7r) (7dd) 306 (1i) (2c) (3a) (4c) (5d) (6d) - (7s),(7w)(7dd) 307 (1i) (2c) (3a) (4c) (5e) (6a) (7a) - - 308 (1i) (2c) (3a) (4c)(5e) (6a) (7b),(7g) - - 309 (1i) (2c) (3a) (4c) (5e) (6c) (7a) - (7dd)310 (1i) (2c) (3a) (4c) (5e) (6c) (7b),(7g) - (7dd) 311 (1i) (2c) (3a)(4c) (5e) (6d) - (7r) (7dd) 312 (1i) (2c) (3a) (4c) (5e) (6d) -(7s),(7w) (7dd) 313 (1i) (2c) (3d) (4b) (5d) (6a) (7a) - - 314 (1i) (2c)(3d) (4b) (5d) (6a) (7b),(7g) - - 315 (1i) (2c) (3d) (4b) (5d) (6c)(7a) - (7dd) 316 (1i) (2c) (3d) (4b) (5d) (6c) (7b),(7g) - (7dd) 317(1i) (2c) (3d) (4b) (5d) (6d) - (7r) (7dd) 318 (1i) (2c) (3d) (4b) (5d)(6d) - (7s),(7w) (7dd) 319 (1i) (2c) (3d) (4b) (5e) (6a) (7a) - - 320(1i) (2c) (3d) (4b) (5e) (6a) (7b),(7g) - - 321 (1i) (2c) (3d) (4b) (5e)(6c) (7a) - (7dd) 322 (1i) (2c) (3d) (4b) (5e) (6c) (7b),(7g) - (7dd)323 (1i) (2c) (3d) (4b) (5e) (6d) - (7r) (7dd) 324 (1i) (2c) (3d) (4b)(5e) (6d) - (7s),(7w) (7dd) 325 (1i) (2c) (3d) (4c) (5d) (6a) (7a) - -326 (1i) (2c) (3d) (4c) (5d) (6a) (7b),(7g) - - 327 (1i) (2c) (3d) (4c)(5d) (6c) (7a) - (7dd) 328 (1i) (2c) (3d) (4c) (5d) (6c) (7b),(7g) -(7dd) 329 (1i) (2c) (3d) (4c) (5d) (6d) - (7r) (7dd) 330 (1i) (2c) (3d)(4c) (5d) (6d) - (7s),(7w) (7dd) 331 (1i) (2c) (3d) (4c) (5e) (6a)(7a) - - 332 (1i) (2c) (3d) (4c) (5e) (6a) (7b),(7g) - - 333 (1i) (2c)(3d) (4c) (5e) (6c) (7a) - (7dd) 334 (1i) (2c) (3d) (4c) (5e) (6c)(7b),(7g) - (7dd) 335 (1i) (2c) (3d) (4c) (5e) (6d) - (7r) (7dd) 336(1i) (2c) (3d) (4c) (5e) (6d) - (7s),(7w) (7dd) 337 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7a) - - 338 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6a) (7b),(7g) - - 339 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7a) - (7dd) 340 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6c) (7b),(7g) - (7dd) 341 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7r) (7dd) 342 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7s),(7w) (7dd) 343 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7a) - - 344 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6a) (7b),(7g) - - 345 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7a) - (7dd) 346 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6c) (7b),(7g) - (7dd) 347 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7r) (7dd) 348 (1i) (2c)(3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7s),(7w) (7dd) 349 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7a) - - 350 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6a) (7b),(7g) - - 351 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7a) - (7dd) 352 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6c) (7b),(7g) - (7dd) 353 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7r) (7dd) 354 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7s),(7w) (7dd) 355 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7a) - - 356 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6a) (7b),(7g) - - 357 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7a) - (7dd) 358 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6c) (7b),(7g) - (7dd) 359 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7r) (7dd) 360 (1i) (2c)(3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7s),(7w) (7dd) 361 (1i) (2g) (3a)(4b) (5d) (6a) (7a) - - 362 (1i) (2g) (3a) (4b) (5d) (6a) (7b),(7g) - -363 (1i) (2g) (3a) (4b) (5d) (6c) (7a) - (7dd) 364 (1i) (2g) (3a) (4b)(5d) (6c) (7b),(7g) - (7dd) 365 (1i) (2g) (3a) (4b) (5d) (6d) - (7r)(7dd) 366 (1i) (2g) (3a) (4b) (5d) (6d) - (7s),(7w) (7dd) 367 (1i) (2g)(3a) (4b) (5e) (6a) (7a) - - 368 (1i) (2g) (3a) (4b) (5e) (6a)(7b),(7g) - - 369 (1i) (2g) (3a) (4b) (5e) (6c) (7a) - (7dd) 370 (1i)(2g) (3a) (4b) (5e) (6c) (7b),(7g) - (7dd) 371 (1i) (2g) (3a) (4b) (5e)(6d) - (7r) (7dd) 372 (1i) (2g) (3a) (4b) (5e) (6d) - (7s),(7w) (7dd)373 (1i) (2g) (3a) (4c) (5d) (6a) (7a) - - 374 (1i) (2g) (3a) (4c) (5d)(6a) (7b),(7g) - - 375 (1i) (2g) (3a) (4c) (5d) (6c) (7a) - (7dd) 376(1i) (2g) (3a) (4c) (5d) (6c) (7b),(7g) - (7dd) 377 (1i) (2g) (3a) (4c)(5d) (6d) - (7r) (7dd) 378 (1i) (2g) (3a) (4c) (5d) (6d) - (7s),(7w)(7dd) 379 (1i) (2g) (3a) (4c) (5e) (6a) (7a) - - 380 (1i) (2g) (3a) (4c)(5e) (6a) (7b),(7g) - - 381 (1i) (2g) (3a) (4c) (5e) (6c) (7a) - (7dd)382 (1i) (2g) (3a) (4c) (5e) (6c) (7b),(7g) - (7dd) 383 (1i) (2g) (3a)(4c) (5e) (6d) - (7r) (7dd) 384 (1i) (2g) (3a) (4c) (5e) (6d) -(7s),(7w) (7dd) 385 (1i) (2g) (3d) (4b) (5d) (6a) (7a) - - 386 (1i) (2g)(3d) (4b) (5d) (6a) (7b),(7g) - - 387 (1i) (2g) (3d) (4b) (5d) (6c)(7a) - (7dd) 388 (1i) (2g) (3d) (4b) (5d) (6c) (7b),(7g) - (7dd) 389(1i) (2g) (3d) (4b) (5d) (6d) - (7r) (7dd) 390 (1i) (2g) (3d) (4b) (5d)(6d) - (7s),(7w) (7dd) 391 (1i) (2g) (3d) (4b) (5e) (6a) (7a) - - 392(1i) (2g) (3d) (4b) (5e) (6a) (7b),(7g) - - 393 (1i) (2g) (3d) (4b) (5e)(6c) (7a) - (7dd) 394 (1i) (2g) (3d) (4b) (5e) (6c) (7b),(7g) - (7dd)395 (1i) (2g) (3d) (4b) (5e) (6d) - (7r) (7dd) 396 (1i) (2g) (3d) (4b)(5e) (6d) - (7s),(7w) (7dd) 397 (1i) (2g) (3d) (4c) (5d) (6a) (7a) - -398 (1i) (2g) (3d) (4c) (5d) (6a) (7b),(7g) - - 399 (1i) (2g) (3d) (4c)(5d) (6c) (7a) - (7dd) 400 (1i) (2g) (3d) (4c) (5d) (6c) (7b),(7g) -(7dd) 401 (1i) (2g) (3d) (4c) (5d) (6d) - (7r) (7dd) 402 (1i) (2g) (3d)(4c) (5d) (6d) - (7s),(7w) (7dd) 403 (1i) (2g) (3d) (4c) (5e) (6a)(7a) - - 404 (1i) (2g) (3d) (4c) (5e) (6a) (7b),(7g) - - 405 (1i) (2g)(3d) (4c) (5e) (6c) (7a) - (7dd) 406 (1i) (2g) (3d) (4c) (5e) (6c)(7b),(7g) - (7dd) 407 (1i) (2g) (3d) (4c) (5e) (6d) - (7r) (7dd) 408(1i) (2g) (3d) (4c) (5e) (6d) - (7s),(7w) (7dd) 409 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6a) (7a) - - 410 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6a) (7b),(7g) - - 411 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6c) (7a) - (7dd) 412 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6c) (7b),(7g) - (7dd) 413 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7r) (7dd) 414 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5d) (6d) - (7s),(7w) (7dd) 415 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5e) (6a) (7a) - - 416 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5e) (6a) (7b),(7g) - - 417 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5e) (6c) (7a) - (7dd) 418 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5e) (6c) (7b),(7g) - (7dd) 419 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7r) (7dd) 420 (1i) (2g) (3g),(3i),(3j),(3k) (4b) (5e) (6d) - (7s),(7w) (7dd) 421 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5d) (6a) (7a) - - 422 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5d) (6a) (7b),(7g) - - 423 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5d) (6c) (7a) - (7dd) 424 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5d) (6c) (7b),(7g) - (7dd) 425 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7r) (7dd) 426 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5d) (6d) - (7s),(7w) (7dd) 427 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5d) (6a) (7a) - - 428 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5e) (6a) (7b),(7g) - - 429 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5e) (6c) (7a) - (7dd) 430 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5e) (6c) (7b),(7g) - (7dd) 431 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7r) (7dd) 432 (1i) (2g) (3g),(3i),(3j),(3k) (4c) (5e) (6d) - (7s),(7w) (7dd)

Embodiment Structural Formula R⁴ R^(4a) R^(4b) R^(4c) 433 (Ib) (6a)(7a) - - 434 (Ib) (6a) (7b),(7g) - - 435 (Ib) (6c) (7a) - (7dd) 436 (Ib)(6c) (7b),(7g) - (7dd) 437 (Ib) (6d) - (7r) (7dd) 438 (Ib) (6d) -(7s),(7w) (7dd) 439 (Ic) (6a) (7a) - - 440 (Ic) (6a) (7b),(7g) - - 441(Ic) (6c) (7a) - (7dd) 442 (Ic) (6c) (7b),(7g) - (7dd) 443 (Ic) (6d) -(7r) (7dd) 444 (Ic) (6d) - (7s),(7w) (7dd) 445 (Id) (6a) (7a) - - 446(Id) (6a) (7b),(7g) - - 447 (Id) (6c) (7a) - (7dd) 448 (Id) (6c)(7b),(7g) - (7dd) 449 (Id) (6d) - (7r) (7dd) 450 (Id) (6d) - (7s),(7w)(7dd) 451 (Ie) (6a) (7a) - - 452 (Ie) (6a) (7b),(7g) - - 453 (Ie) (6c)(7a) - (7dd) 454 (Ie) (6c) (7b),(7g) - (7dd) 455 (Ie) (6d) - (7r) (7dd)456 (Ie) (6d) - (7s),(7w) (7dd)

Embodiment Structural Formula R⁴ R^(4a) R^(4c) 457 (Ic) (6a) (7b) - 458(Ic) (6a) (7g) - 459 (Ic) (6a) (7n) - 460 (Ic) (6a) (7p) - 461 (Ic) (6a)(7q) - 462 (Ic) (6a) (7gg) - 463 (Ic) (6c) (7g) (7dd) 464 (Id) (6a)(7b) - 465 (Id) (6a) (7g) - 466 (Id) (6a) (7n) - 467 (Id) (6a) (7p) -468 (Id) (6a) (7q) - 469 (Id) (6a) (7gg) - 470 (Id) (6c) (7g) (7dd) 471(Ie) (6a) (7b) - 472 (Ie) (6a) (7n) - 473 (Ie) (6a) (7g) - 474 (Ie) (6a)(7p) - 475 (Ie) (6a) (7q) - 476 (Ie) (6a) (7gg) - 477 (Ie) (6c) (7g)(7dd)

In certain additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above, each optionally substituted alkyl, alkenyl, and alkynylrecited in any one of preceding embodiments is unsubstituted. Inalternative additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above, each optionally substituted alkyl, alkenyl, and alkynylrecited in any one of preceding embodiments is independently substitutedor unsubstituted. In further alternative additional embodiments,including any of the embodiments described with reference to formulae(I), (la)-(le) and embodiments 1-477 above, each optionally substitutedalkyl, alkenyl, and alkynyl recited in any one of preceding embodimentsis substituted.

In certain additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above and the embodiment described in the paragraph immediatelyabove, each cycloalkyl recited in any one of the preceding embodimentsis a 3-7 membered monocyclic cycloalkyl. For example, in certainparticular embodiments, including any of the embodiments described withreference to formulae (I), (la)-(le) and embodiments 1-477 above and theembodiment described in the paragraph immediately above, each cycloalkylrecited in any one of the preceding embodiments is a cyclopropyl, acyclobutyl, a cyclopentyl, a cyclopentenyl, a cyclohexyl or acyclohexenyl.

In certain additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above and any embodiment described in the two paragraphsimmediately above, each heterocycloalkyl recited in any one of thepreceding embodiments is a 4-7 membered monocyclic heterocycloalkylhaving 1-2 heteroatoms selected from O, S and N. For example, in certainparticular embodiments, including any of the embodiments described withreference to formulae (I), (la)-(le) and embodiments 1-477 above and anyembodiment described in the two paragraphs immediately above, eachheterocycloalkyl recited in any one of the preceding embodiments is apyrrolidinyl, a tetrahydrofuranyl, a tetrahydrothienyl, a piperidinyl, apiperazinyl, a morpholinyl, a thiomorpholinyl, a tetrahydro-2H-pyranyl,or a tetrahydro-2H-thiopyranyl. In certain particular embodiments,including any of the embodiments described with reference to formulae(I), (la)-(le) and embodiments 1-477 above and any embodiment describedin the two paragraphs immediately above, each heterocycloalkyl recitedin any one of the preceding embodiments is a pyrrolidine, a piperidine,a piperazine, a tetrahydrofuran, a (1H)dihydropyran, or a morpholine(e.g., each unsubstituted).

In certain additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above and any embodiment described in the three paragraphsimmediately above, each aryl is phenyl.

In certain additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above and any embodiment described in the four paragraphsimmediately above, each heteroaryl is a 5-6 membered monocyclicheteroaryl having 1-3 heteroatoms selected from O, S and N. For example,in certain particular embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above and any embodiment described in the four paragraphsimmediately above, each heteroaryl is a monocyclic heteroaryl issubstituted with 0-3 R⁸, e.g., is unsubstituted, substituted with one R⁸or substituted with two R⁸. In certain particular embodiments, includingany of the embodiments described with reference to formulae (I),(la)-(le) and embodiments 1-477 above and any embodiment described inthe four paragraphs immediately above, each heteroaryl is a furanyl, athienyl, a pyrrolyl, a pyrazolyl, an imidazolyl, an oxazolyl or athiazolyl.

In certain additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above and any embodiment described in the paragraphs immediatelyabove, each R⁷ is independently oxo, C₁-C₄ alkyl, CI, F, Br, -CN, -SF₅,-N₃, nitro, -SR^(A), -S(O)₁₋₂R^(A), -OR^(A), -NR^(B)R^(A), -C(O)R^(A),-C(O)NR^(B)R^(A), -NR^(B)C(O)R^(A), -C(S)NR^(B)R^(A), -NR^(B)C(S)R^(A),-CO₂R^(A), -OC(O)R^(A), -C(O)SR^(A), -SC(O)R^(A), -C(S)OR^(A),-OC(S)R^(A), -C(S)SR^(A), -SC(S)R^(A), -S(0)₁₋₂OR^(A), -OS(O)₁₋₂R^(A),-S(O)₁₋₂NR^(B)R^(A), or -NR^(B)S(O)₁₋₂R^(A). For example, in certainadditional embodiments, including any of the embodiments described withreference to formulae (I), (la)-(le) and embodiments 1-477 above and anyembodiment described in the paragraphs immediately above, each R⁷ isindependently oxo, C₁-C₄ alkyl, CI, F, Br, -CN, -SF₅, -N₃, nitro,-SR^(A), -S(O)₁₋₂R^(A), -OR^(A), -NR^(B)R^(A), or -C(O)R^(A).

In certain additional embodiments, including any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above and any embodiment described in the paragraphs immediatelyabove, each R⁸ is independently C₁-C₄ alkyl, CI, F, Br, -CN, -SF₅, -N₃,nitro, -SR^(A), -S(O)₁₋₂R^(A), -OR^(A), -NR^(B)R^(A), -C(O)R^(A),-C(O)NR^(B)R^(A), -NR^(B)C(O)R^(A), -C(S)NR^(B)R^(A), -NR^(B)C(S)R^(A),-CO₂R^(A), -OC(O)R^(A), -C(O)SR^(A),-SC(O)R^(A), -C(S)OR^(A),-OC(S)R^(A), -C(S)SR^(A), -SC(S)R^(A), -S(O)₁₋₂OR^(A), -OS(O)₁₋₂R^(A),-S(O)₁₋₂NR^(B)R^(A), or -NR^(B)S(O)₁₋₂R^(A). In certain additionalembodiments, including any of the embodiments described with referenceto formulae (I), (la)-(le) and embodiments 1-477 above and anyembodiment described in the paragraphs immediately above, each R⁸ isindependently C₁-C₄ alkyl, Cl, F, Br, -CN, SF₅, -N₃, nitro, -SR^(A),-S(O)₁₋₂R^(A), -OR^(A), -NR^(B)R^(A), or -C(O)R^(A).

In some embodiments, the present disclosure relates in particular to acompound selected from:

-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonic    acid;-   sodium    3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonate;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(methylsulfonyl)-5-pentylbenzene-1,3-diol;-   4-(cyclopropylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   4-(tert-butylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   4-(benzylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(phenylsulfonyl)benzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-4-((4-nitrophenyl)sulfonyl)-5-pentylbenzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyridin-3-ylsulfonyl)benzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(furan-3-ylsulfonyl)-5-pentylbenzene-1,3-diol;-   4-((1H-imidazol-4-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(oxetan-3-ylsulfonyl)-5-pentylbenzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-((perfluorophenyl)sulfonyl)benzene-1,3-diol;-   4-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)cyclohexan-1-one;-   1-(2-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)ethyl)pyrrolidine-2,5-dione;-   4-((2-(dimethylamino)ethyl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   1-(3-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)piperidin-1-yl)ethan-1-one;-   4-((2-chloropyrimidin-5-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-methyl-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N,N-dimethyl-6-pentylbenzenesulfonamide;-   N-cyclopropyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-    1-yl)-2,4-dihydroxy-N-isopropyl-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-phenylbenzenesulfonamide;-   N-benzyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-    3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyrimidin-2-yl)benzenesulfonamide    ;-   4-((4-methylpiperazin-1-yl)sulfonyl)-5-pentylbenzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(piperidin-1-ylsulfonyl)benzene-1,3-diol;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(morpholinosulfonyl)-5-pentylbenzene-1,3-diol;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyridin-3-yl)benzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-(2-oxopropyl)-6-pentylbenzenesulfonamide;-   1-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)azetidin-3-one;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-(oxetan-2-ylmethyl)-6-pentylbenzenesulfonamide;-   4-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   4-((2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;-   ((3-(3,7-dimethylocta-2,6-dien-    1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)alanine;-   methyl    ((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)alaninate;-   N-((3-(3,7-dimethylocta-2,6-d    ien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-morpholinopropanamide;-   4-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonamido)-4-oxobutanoic    acid;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-(4-methylpiperazin-1-yl)propanamide;-   2-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide;-   N-((3-(3,7-dimethylocta-2,6-d    ien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(2-methoxyethoxy)acetamide;-   2-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-hydroxypropanamide;-   2-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)propanamide;-   3-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-methylpropanamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-oxobutanamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(3-methyl-1H-1    ,2,4-triazol-5-yl)acetamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-1H-1,2,4-triazole-5-carboxamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)oxetane-2-carboxamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)benzamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)nicotinamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-phenylacetamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(furan-2-yl)acetamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(oxazol-2-yl)acetamide;-   N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(thiazol-2-yl)acetamide;-   2-(1H-benzo[d]imidazol-2-yl)-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(phenylsulfonyl)benzamide;-   N-(cyclohexylsulfonyl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-((prop-1-en-1-yl)sulfonyl)benzamide;-   N-((1H-benzo[d]imidazol-2-yl)sulfonyl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzamide;-   N-cyclohexyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   N-cyclobutyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-    1-yl)-N-hexyl-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   N-allyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-    1-yl)-2,4-dihydroxy-6-pentyl-N-(pyridin-3-ylsulfonyl)bnzamide; and-   phenyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonate.

In some embodiments, the present disclosure further relates inparticular to a compound selected from:

-   2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(methylsulfonyl)-5-pentylbenzene-1,3-diol;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-methyl-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-isopropyl-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-phenylbenzenesulfonamide;-   2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(morpholinosulfonyl)-5-pentylbenzene-1,3-diol;-   3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(phenylsulfonyl)benzamide;-   N-cyclohexyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   N-cyclobutyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-    1-yl)-N-hexyl-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   N-allyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;-   3-(3,7-dimethylocta-2,6-dien-    1-yl)-2,4-dihydroxy-6-pentyl-N-(pyridin-3-ylsulfonyl)benzamide; and-   phenyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonate.

In certain embodiments of the compounds as otherwise described herein,the compound is in the form of a pharmaceutically acceptable salt of thecompound as described herein or an enantiomer, diastereomer, racemate,tautomer, or metabolite thereof. The person of ordinary skill in the artwill appreciate that a variety of pharmaceutically-acceptable salts maybe provided, such as for example described in additional detail below.

In certain embodiments of the compounds as otherwise described herein, acompound is in the form of a solvate (e.g., a hydrate) of a compound asdescribed herein, or an enantiomer, diastereomer, racemate, tautomer, ormetabolite thereof. The person of ordinary skill in the art willappreciate that a variety of solvates and/or hydrates may be formed.

The person of ordinary skill in the art will appreciate that the phrase“or an enantiomer, diastereomer, racemate, tautomer, or metabolitethereof, or a pharmaceutically acceptable salt, solvate or hydrate ofthe compound, enantiomer, diastereomer, racemate, tautomer, ormetabolite” includes compounds in the form of salts, solvates, hydratesof the base compounds (including its enantiomers, diastereomers,racemates, or tautomers) or a metabolite of the base compound. But incertain embodiments as described above, the compound is not in the formof a salt, solvate or hydrate.

Therapeutics Applications

In some embodiments, compounds of the present disclosure have anaffinity for at least one cannabinoid receptor (e.g. CB1, CB2, 5HT1A,5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARs (such as PPARγ), or aµ-opioid receptor). Thus, in another aspect, the present disclosurerelates to the use of at least one of the compounds of the presentdisclosure to bind and/or interact with a cannabinoid receptor.

In some embodiments, compounds of the present disclosure may have anaffinity for one or both of the CB1 receptor and CB2 receptor. In aparticular embodiment, compounds of the present disclosure may have anaffinity for the CB1 receptor, but not the CB2 receptor. In a particularembodiment, compounds of the present disclosure may have an affinity forthe CB2 receptor, but not the CB1 receptor.

In some embodiments, compounds of the present disclosure may exhibit aselectivity for one receptor over another. As used herein, by“selectivity” it is meant that a compound binds, interacts with, ormodulates preferentially one receptor over another. In an embodiment, acompound is selective for one receptor over another if its affinity forone receptor is at least 1.25-fold, at least 1.5-fold, at least 2-fold,at least 5-fold, at least 10-fold, at least 25-fold, at least 50-fold,or at least 100-fold greater for the one receptor than another receptor.In an embodiment, the affinity of a compound as disclosed herein for areceptor may be determined by a radioligand competitive binding assay,such as for example described in the examples herein.

In some embodiments, compounds of the present disclosure may have anaffinity for the CB1 receptor, with selectivity for the CB1 receptorover the CB2 receptor.

In some embodiments, compounds of the present disclosure may have anaffinity for the CB2 receptor, with selectivity for the CB2 receptorover the CB1 receptor.

In some embodiments, compounds of the present disclosure may function asan agonist, a partial agonist, an indirect agonist, an antagonist, aninverse agonist, a neutral agonist, or an allosteric modulator to atleast one cannabinoid receptor (e.g. CB1, CB2, 5HT1A, 5HT2A, GPR18,GPR55, GPR119, TRPV1, TPRV2, PPARs (such as PPARγ), or a µ-opioidreceptor). In some embodiments, compounds of the present disclosure mayfunction as an agonist, a partial agonist, an indirect agonist,antagonist, inverse agonist, neutral agonist, or allosteric modulator tothe CB1 and/or CB2 receptor. In some embodiments, compounds of thepresent disclosure may function as an agonist to the CB1 and/or CB2receptor. In some embodiments, compounds of the present disclosure mayfunction as an antagonist to the CB1 and/or CB2 receptor. In someembodiments, compounds of the present disclosure may function as anindirect agonist to the 5HT1A receptor.

In some embodiments, compounds of the present disclosure may act as aprodrug to a compound (e.g. a metabolite) that functions as an agonist,a partial agonist, an indirect agonist, an antagonist, an inverseagonist, or a neutral agonist to at least one of the cannabinoidreceptors (e.g. CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1,TPRV2, PPARs (e.g. PPARγ), or a µ-opioid receptor).

The present disclosure further relates to use of a compound as disclosedherein as a therapeutically active substance or as a prodrug to atherapeutically active substance.

In an embodiment, the present disclosure relates to the use of acompound as disclosed herein for the treatment or prevention of adisease associated with a cannabinoid receptor (e.g. CB1, CB2, 5HT1A,5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARs (e.g. PPARγ), or aµ-opioid receptor). In an embodiment, by “disease associated with acannabinoid” it is meant to refer to a disease, disorder or conditionthat is treatable or preventable by acting on a cannabinoid receptor(e.g. CB1, CB2, 5HT1A, 5HT2A, GPR18, GPR55, GPR119, TRPV1, TPRV2, PPARs(e.g. PPARγ), or a µ-opioid receptor). In an embodiment, compounds ofthe present disclosure may treat or prevent the condition by acting asan agonist, partial agonist, antagonist, inverse agonist, neutralagonist, or an allosteric modulator to the cannabinoid receptor or as aprodrug of a compound (e.g. metabolite) that acts as an agonist, partialagonist, antagonist, inverse agonist, neutral agonist, or allostericmodulator to the cannabinoid receptor. In select embodiments, thecannabinoid receptor is CB1 or CB2.

In an embodiment, the present disclosure relates to the use of acompound as disclosed herein for selectively modulating the activity ofone receptor over another receptor. In an embodiment, at least one ofthe receptors is a cannabinoid receptor. In an embodiment, bothreceptors are a cannabinoid receptor. In an embodiment, the receptorsare CB1 and CB2. In select embodiments, the present disclosure relatesto the use of a compound as disclosed herein for selectively modulatingthe activity of a CB1 or CB2 receptor.

As used herein, by “selectively modulating” it is intended to refer tothe ability of the compounds of the present disclosure to cause anychange in activity of the receptor. In an embodiment, “selectivelymodulating” means to stimulate or inhibit the activity of the receptor,either directly or indirectly.

The disclosure also relates to methods of treating or preventing adisease,, such as a disease associated with a cannabinoid receptor (e.g.CB1 and/or CB2). These methods include administering to a subject inneed of such treatment or prevention a therapeutically effective amountof one or more compounds of the disclosure as described herein (e.g.,compounds of formula (I)) or a pharmaceutical composition of thedisclosure as described herein.

In certain embodiments, the diseases of the disclosure include, but arenot limited to ADHD/ADD, alcohol use disorder, allergic asthma, ALS,Alzheimer’s, anorexia (e.g. HIV-related cachexia), anxiety disorders(e.g., social anxiety disorder, specific phobia, test anxiety,generalized anxiety disorder), arthritis, atherosclerosis, autism,bipolar disorder, burns, cancer, cancer pain, Charcot-Marie-Toothdisease, chronic inflammatory demyelinating polyneuropathies, chronicallograft nephropathy, cocaine use disorder, complex regional painsyndrome, congestive heart failure, depression, fibromyalgia, fragile Xsyndrome/FXTAS, frontotemporal dementias (behavioural variant),gingivitis pyrexia, glaucoma, glioblastoma, glomerulonephropathy,Huntington’s disease, hypertrophic scars, IBD/IBS, inflammation,Inflammatory myopathies, ischemia, kidney fibrosis, keloids,leukodystrophies, liver fibrosis, liver cirrhosis, lung fibrosis,migraine, multiple sclerosis, myocardial infarction, nausea (e.g. CINV,motion sickness), neuropathic pain (e.g., postherpetic neuralgia,painful diabetic neuropathy), nightmare disorder, non-alcoholic fattyliver disease, obesity, obsessive-compulsive disorder, opioid sparing,opioid use disorder, osteoarthritis, osteoporosis, pain (e.g. acute orchronic pain), Parkinson’s, post-concussion syndrome/traumatic braininjury, psychosis/schizophrenia, PTSD, regulation of bone mass, REMsleep behaviour disorder, reperfusion injury, Rett syndrome, rheumatoidarthritis, skin conditions (e.g. acne, psoriatic arthritis), sleepdisorders (e.g., insomnia, RLS), spinocerebellar ataxias, systemicfibrosis, systemic sclerosis, thermal injury, tobacco usedisorder/nicotine dependence, Tourette’s, tumors, and trigeminalneuralgia.

The compounds and compositions of the disclosure as described herein mayalso be administered in combination with one or more secondarytherapeutic agents. Thus, in certain embodiment, the method alsoincludes administering to a subject in need of such treatment orprevention a therapeutically effective amount of one or more compoundsof the disclosure as described herein or a pharmaceutical composition ofthe disclosure as described herein and one or more secondary therapeuticagents. Examples of suitable secondary therapeutic agents include, butare not limited to, temozolomide, camptothecin, doxorubicin,daunorubicin, vincristine, paclitaxel, neocarzinostatin, calicheamicin,cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin,lurtotecan, annamycin, docetaxel, tamoxifen, epirubicin, methotrexate,vinblastin, vincristin, topotecan, prednisone, prednisolone,chloroquine, hydroxychloroquine, autophagy inhibitors, abt-737,leucovorin, psilocybin, psilocin, psiloacetin, netupitant, palonosetron,aprepitant, 3,4-methylenedioxymethamphetamine, nicotine, ketamine,lithium salts (e.g., lithium citrate), valproic acid, bevacizumab,bortezomib, fluorouracil, gemcitabine, irinotecan, oxaliplatin,adalimumab, azathioprine, infliximab, citalopram, mirtazapine,sertraline, esketamine, fluoxetine, paroxetine, venlafaxine,fenfluramine, vigabatrin, bupropion, atomoxetine, memantine, clobazam,stiripentol, cyclosporine, tacrolimus, methylprednisolone, megestrolacetate, biguanides (e.g., metformin), sulphonyl ureas (e.g., glipizide,tolbutamide), gabapentin, baclofen, clonazepam, dantrolene, diazepam,tizanidine, buprenorphine, naltrexone, opioids (e.g., codeine,oxycodone, morphine), amisulpride, aripiprazole, olanzapine, quetiapine,risperidone, clonidine, lomazenil, benzodiazepine, benzamide,dexamethasone, gemcitabine, and palmitoylethanolamide. When administeredas a combination, the compounds and compositions of the disclosure asdescribed herein and the secondary therapeutic agents can be formulatedas separate compositions that are given simultaneously or sequentially,or the therapeutic agents can be given as a single composition. Incertain embodiments, the secondary therapeutic agent may be administeredin an amount below its established half maximal inhibitory concentration(IC₅₀). For example, the secondary therapeutic agent may be administeredin an amount less than 1% of, e.g., less than 10%, or less than 25%, orless than 50%, or less than 75%, or even less than 90% of the inhibitoryconcentration (IC₅₀).

Prodrugs

In some embodiments, a compound as described herein may itself be aprodrug or may be further modified to provide a prodrug.

Prodrugs in accordance with the present disclosure may, for example, beproduced by replacing appropriate functionalities present in thecompounds disclosed herein, such as for example any of the embodimentsdescribed with reference to formulae (I), (la)-(le) and embodiments1-477 above, with certain moieties known to those skilled in the art as“promoieties” as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985) and Y.M. Choi-Sledeski and C.G. Wermuth,Designing Prodrugs and Bioprecursors in Practice of Medicinal Chemistry,(Fourth Edition), Chapter 28, 657-696 (Elsevier, 2015).

In exemplary embodiments, a prodrug in accordance with the presentdisclosure is (a) an ester or amide derivative of a carboxylic acid in acompound disclosed herein; (b) an ester, carbonate, carbamate, acetal,aminal, phosphate, or ether derivative of a hydroxyl group in a compounddisclosed herein; (c) an amide, imine, carbamate or amine derivative ofan amino group in a compound disclosed herein; (d) an oxime or iminederivative of a carbonyl group in a compound disclosed herein; or (e) amethyl, primary alcohol or aldehyde group that can be metabolicallyoxidized to a carboxylic acid in a compound disclosed herein.

Certain compounds of the present disclosure, such as for example any ofthe embodiments described with reference to formulae (I), (la)-(le) andembodiments 1-477 above, may themselves act as prodrugs. In anembodiment, a compound of the present disclosure, such as for exampleany of the embodiments described with reference to formulae (I),(la)-(le) and embodiments 1-477 above, may act as a prodrug of acannabinoid, such as for example a natural cannabinoid (e.g. CBD orCBDA).

References to compounds disclosed herein are taken to include thecompounds themselves and prodrugs thereof. The present disclosureincludes such prodrug compounds as well as any pharmaceuticallyacceptable salts of such prodrug compounds, and/or any solvates,hydrates, enantiomers, diastereomers, racemates, tautomers, ormetabolites of such prodrug compounds and their salts.

In some embodiments, a prodrug compound of the present disclosure mayexhibit improved pharmacokinetics (PK), improved biodistribution, and/orimproved formulation capabilities (e.g. stability in formulation). Forexample, in an embodiment, these characteristics may be improved overnatural cannabinoids (e.g. CBD or CBDA).

In some embodiments, a prodrug compound of the present disclosure mayexhibit unique or improved biological activity. For example, in anembodiment, these characteristics may be unique or improved over naturalcannabinoids (e.g. CBD or CBDA).

Pharmaceutical Compositions and Dosage Forms

A compound as described herein can usefully be provided in the form of apharmaceutical composition. Such compositions include the compoundaccording to any one of the preceding aspects or embodiments describedherein, together with a pharmaceutically acceptable excipient, diluent,or carrier.

The compounds may be formulated in the pharmaceutical composition perse, or in the form of a hydrate, solvate, or pharmaceutically acceptablesalt, as previously described. Typically, such salts are more soluble inaqueous solutions than the corresponding free acids and bases, but saltshaving lower solubility than the corresponding free acids and bases mayalso be formed.

The pharmaceutical composition can be, for example, in the form of atablet, a capsule, or a parenteral formulation, but the person ofordinary skill in the art will appreciate that the compound can beprovided in a wide variety of pharmaceutical compositions.

The compounds of the disclosure can be administered, for example,orally, topically, parenterally, by inhalation or spray or rectally indosage unit formulations containing one or more pharmaceuticallyacceptable carriers, diluents or excipients. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. A medicament including a compound of thedisclosure can be provided, for example, in any of the formulations anddosage forms as described herein.

Pharmaceutical compositions can be made using the presently disclosedcompounds. For example, in one embodiment, a pharmaceutical compositionincludes a pharmaceutically acceptable carrier, diluent or excipient,and compound as described above with reference to any one of structuralformulae.

In the pharmaceutical compositions disclosed herein, one or morecompounds of the disclosure may be present in association with one ormore pharmaceutically acceptable carriers, diluents or excipients, and,if desired, other active ingredients. The pharmaceutical compositionscontaining compounds of the disclosure may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use can be prepared according to anysuitable method for the manufacture of pharmaceutical compositions andsuch compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreservative agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients can be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets can be uncoated or they can be coated by known techniques. Insome cases such coatings can be prepared by suitable techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed.

Formulations for oral use can also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use can also be presented as lozenges.

Formulations for oral use can also be presented as beverages or edibles.For example, in an embodiment, the compounds of the present disclosuremay be presented in water-soluble formulations such as disclosed inPCT/CA2019/051698, comprising an emulsifier and a glycerin-based carriersurfactant. In other embodiments, the compounds of the presentdisclosure may be presented in compositions such as disclosed inPCT/CA2019/051704, comprising inulin and pectin.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients can be suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, can also be present.

Pharmaceutical compositions can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil or a mineral oil ormixtures of these. Suitable emulsifying agents can benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions can also containsweetening and flavoring agents.

In some embodiments, the pharmaceutically acceptable carrier, diluent,or excipient is not water. In other embodiments, the water comprisesless than 50% of the composition. In some embodiments, compositionscomprising less than 50% water have at least 1%, 2%, 3%, 4% or 5% water.In other embodiments, the water content is present in the composition ina trace amount.

In some embodiments, the pharmaceutically acceptable carrier, diluent,or excipient is not alcohol. In other embodiments, the alcohol comprisesless than 50% of the composition. In some embodiments, compositionscomprising less than 50% alcohol have at least 1%, 2%, 3%, 4% or 5%alcohol. In other embodiments, the alcohol content is present in thecomposition in a trace amount.

Syrups and elixirs can be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations can also contain a demulcent, a preservative, flavoring,and coloring agents. The pharmaceutical compositions can be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension can be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer’s solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils can be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.

Compounds of the disclosure can also be administered in the form ofsuppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the compound with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of the disclosure can also be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

The compositions can be formulated in a unit dosage form of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The compound can be effective over a wide dosage range and is generallyadministered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated orprevented, the chosen route of administration, the actual compoundadministered, the age, weight, and response of the individual patient,the severity of the patient’s symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of acompound described herein.

The tablets or pills can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permit the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated orprevented as well as by the judgment of the attending cliniciandepending upon factors such as the severity of the disease, the age,weight and general condition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds can vary according to, forexample, the particular use for which the treatment is made, the mannerof administration of the compound, the health and condition of thepatient, and the judgment of the prescribing physician. The proportionor concentration of a compound described herein in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds described herein can beprovided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 µg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

The compounds described herein can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

The person of ordinary skill in the art will formulate a compound asdescribed into pharmaceutical formulations herein. For example, based onthe physicochemical properties of the compound, the amount of thecompound needed for a therapeutically effective amount, and the desiredroute of administration.

Definitions

Terms used herein may be preceded and/or followed by a single dash, “-”,or a double dash, “=”, to indicate the bond order of the bond betweenthe named substituent and its parent moiety; a single dash indicates asingle bond and a double dash indicates a double bond or a pair ofsingle bonds in the case of a spiro-substituent. In the absence of asingle or double dash it is understood that a single bond is formedbetween the substituent and its parent moiety; further, substituents areintended to be read “left to right” with reference to the chemicalstructure referred to unless a dash indicates otherwise. For example,arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality.

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietycan refer to a monovalent radical (e.g. CH₃—CH₂—), in some circumstancesa bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂), which is equivalent to the term “alkylene.” (Similarly, incircumstances in which a divalent moiety is required and is stated asbeing “aryl,” those skilled in the art will understand that the term“aryl” refers to the corresponding divalent moiety, arylene). All atomsare understood to have their normal number of valences for bondformation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S,depending on the oxidation state of the S). Nitrogens in the presentlydisclosed compounds can be hypervalent, e.g., an N-oxide ortetrasubstituted ammonium salt. On occasion a moiety may be defined, forexample, as -B-(A)_(a), wherein a is 0 or 1. In such instances, when ais 0 the moiety is -B and when a is 1 the moiety is -B-A.

As used herein, the term “alkyl” includes a saturated hydrocarbon havinga designated number of carbon atoms, such as 1 to 10 carbons (i.e.,inclusive of 1 and 10), 1 to 8 carbons, 1 to 6 carbons, 1 to 3 carbons,or 1, 2, 3, 4, 5 or 6. Alkyl group may be straight or branched anddepending on context, may be a monovalent radical or a divalent radical(i.e., an alkylene group). For example, the moiety “-(C₁-C₆ alkyl)-O-”signifies connection of an oxygen through an alkylene bridge having from1 to 6 carbons and C₁-C₃ alkyl represents methyl, ethyl, and propylmoieties. Examples of “alkyl” include, for example, methyl, ethyl,propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, and hexyl.

The term “alkoxy” represents an alkyl group of indicated number ofcarbon atoms attached to the parent molecular moiety through an oxygenbridge, such as alkyl-O- in which the term “alkyl” has the previouslygiven definition. Examples of “alkoxy” include, for example, methoxy,ethoxy, propoxy, and isopropoxy.

The term “alkenyl”, as used herein, represents an unsaturatedhydrocarbon having a designated number of carbon atoms, such as 2 to 10carbons (i.e., inclusive of 2 and 10), 2 to 8 carbons, 2 to 6 carbons,or 2, 3, 4, 5 or 6, unless otherwise specified, and containing at leastone carbon-carbon double bond. Alkenyl group may be straight or branchedand depending on context, may be a monovalent radical or a divalentradical (i.e., an alkenylene group). For example, the moiety“-(C₂-C₆alkenyl)-O-” signifies connection of an oxygen through analkenylene bridge having from 2 to 6 carbons. Representative examples ofalkenyl include, but are not limited to, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

The term “alkynyl”, as used herein, represents an unsaturatedhydrocarbon having a designated number of carbon atoms, such as 2 to 10carbons (i.e., inclusive of 2 and 10), 2 to 8 carbons, 2 to 6 carbons,or 2, 3, 4, 5 or 6 unless otherwise specified, and containing at leastone carbon-carbon triple bond. Alkynyl group may be straight or branchedand depending on context, may be a monovalent radical or a divalentradical (i.e., an alkynylene group). For example, the moiety“-(C₂-C₆alkynyl)-O-” signifies connection of an oxygen through analkynylene bridge having from 2 to 6 carbons. Representative examples ofalkynyl include, but are not limited to, acetylenyl, 1-propynyl,2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” represents an aromatic ring system having a single ring(e.g., phenyl) which is optionally fused to other aromatic hydrocarbonrings or non-aromatic hydrocarbon or heterocycle rings. “Aryl” includesring systems having multiple condensed rings and in which at least oneis carbocyclic and aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl,naphthyl). Examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl,and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. “Aryl” also includesring systems having a first carbocyclic, aromatic ring fused to anonaromatic heterocycle, for example, 1H-2,3-dihydrobenzofuranyl andtetrahydroisoquinolinyl. The aryl groups herein are unsubstituted or,when specified as “optionally substituted”, can unless stated otherwisebe substituted in one or more substitutable positions with variousgroups as indicated.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, andiodine. In certain embodiments of each and every embodiment as otherwisedescribed herein, the term “halogen” or “halo” refers to fluorine orchlorine. In certain embodiments of each and every embodiment describedherein, the term “halogen” or “halo” refers to fluorine. The term“fluoroalkyl” indicates an alkyl group (i.e., as otherwise describedherein) that is substituted with at least one fluorine. “Fluoroalkyl”includes alkyl groups substituted with multiple fluorines, such asperfluoroalkyl groups. Examples of fluoroalkyl groups includefluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoroprop-2-yl and2,2,3,3,3-pentafluoroprop-1-yl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one aromatic heteroatom selected from nitrogen, oxygen and sulfurin an aromatic ring. Most commonly, the heteroaryl groups will have 1,2, 3, or 4 heteroatoms. The heteroaryl may be fused to one or morenon-aromatic rings, for example, cycloalkyl or heterocycloalkyl rings,wherein the cycloalkyl and heterocycloalkyl rings are described herein.In one embodiment of the present compounds the heteroaryl group isbonded to the remainder of the structure through an atom in a heteroarylgroup aromatic ring. In another embodiment, the heteroaryl group isbonded to the remainder of the structure through a non-aromatic ringatom. Examples of heteroaryl groups include, for example, pyridyl,pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl,pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl,isochromanyl, chromanyl, isoindolinyl, isobenzothienyl, benzoxazolyl,pyridopyridinyl, purinyl, benzodioxolyl, triazinyl, pteridinyl,benzothiazolyl, imidazopyridinyl, imidazothiazolyl, benzisoxazinyl,benzoxazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl,pyridinyl-N-oxide, isoindolinonyl, benzodioxanyl, benzoxazolinonyl,pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinylN-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide,isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide,phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolylN-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide,oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolylN-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide.Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl,indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl,indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, eachheteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolylN-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolylN-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups includepyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl,imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. Theheteroaryl groups herein are unsubstituted or, when specified as“optionally substituted”, can unless stated otherwise be substituted inone or more substitutable positions with various groups, as indicated.

The term “heterocycloalkyl” refers to a non-aromatic ring or ring systemcontaining at least one heteroatom that is preferably selected fromnitrogen, oxygen and sulfur, wherein said heteroatom is in anon-aromatic ring. The heterocycloalkyl may have 1, 2, 3 or 4heteroatoms. The heterocycloalkyl may be saturated (i.e., aheterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl).Heterocycloalkyl includes monocyclic groups of three to eight annularatoms as well as bicyclic and polycyclic ring systems, including bridgedand fused systems, wherein each ring includes three to eight annularatoms. The heterocycloalkyl ring is optionally fused to otherheterocycloalkyl rings and/or non-aromatic hydrocarbon rings. In certainembodiments, the heterocycloalkyl groups have from 3 to 7 members in asingle ring. In other embodiments, heterocycloalkyl groups have 5 or 6members in a single ring. In some embodiments, the heterocycloalkylgroups have 3, 4, 5, 6 or 7 members in a single ring. Examples ofheterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (ineach case also “quinuclidinyl” or a quinuclidine derivative),azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl,pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxideand homothiomorpholinyl S-oxide. Especially desirable heterocycloalkylgroups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl,tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl,y-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl),y-butryolactamyl (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl,piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinylS,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl,piperazinonyl. The heterocycloalkyl groups herein are unsubstituted or,when specified as “optionally substituted”, can unless stated otherwisebe substituted in one or more substitutable positions with variousgroups, as indicated.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ringsystem, which may be saturated (i.e., a cycloalkyl) or partiallyunsaturated (i.e., a cycloalkenyl). The cycloalkyl ring may beoptionally fused to or otherwise attached (e.g., bridged systems) toother cycloalkyl rings. Certain examples of cycloalkyl groups of thepresent disclosure have from 3 to 7 members in a single ring, such ashaving 5 or 6 members in a single ring. In some embodiments, thecycloalkyl groups have 3, 4, 5, 6 or 7 members in a single ring.Examples of cycloalkyl groups include, for example, cyclohexyl,cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl andbicyclo[2.2.1]heptane. The cycloalkyl groups herein are unsubstitutedor, when specified as “optionally substituted”, may be substituted inone or more substitutable positions with various groups, as indicated.

The term “ring system” encompasses monocycles, as well as fused and/orbridged polycycles.

The term “amino” signifies the primary amino group, the secondary aminogroup, or the tertiary amino group, as context dictates.

The term “carbonyl” signifies the —C(O)— group.

The terms “hydroxy” and “hydroxyl” signify the —OH group.

The term “oxo” means a doubly bonded oxygen, sometimes designated as ═Oor for example in describing a carbonyl “C(O)” may be used to show anoxo substituted carbon.

The term “oxy” signifies the —O— group.

The term “sulfonyl” signifies the —SO₂— group.

The term “substituted,” when used to modify a specified group orradical, means that one or more hydrogen atoms of the specified group orradical are each, independently of one another, replaced with the sameor different substituent groups as defined below, unless specifiedotherwise.

As used herein, the term “metabolite” means a compound that results fromthe metabolism of a compound of the present disclosure, including fromany of the embodiments described with reference to formulae (I),(la)-(le) and embodiments 1-477 above. In an embodiment, the metaboliteis an active metabolite meaning that it is a physiologically activecompound. In an embodiment, the metabolite is an active compoundobtained from metabolism of a prodrug as described herein.

The term “pharmaceutically acceptable” is meant as reference to acompound, substance or composition that is generally safe, non-toxic andbiologically acceptable.

As used herein, the phrase “pharmaceutically acceptable salt” refers toboth pharmaceutically acceptable acid and base addition salts. Suchpharmaceutically acceptable salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where nis 0-4, and the like. Non-toxic pharmaceutical base addition saltsinclude salts of bases such as sodium, potassium, calcium, ammonium, andthe like. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

One of ordinary skill in the art of medicinal chemistry also willappreciate that the disclosed structures are intended to includeisotopically enriched forms of the present compounds. As used herein“isotopes” includes those atoms having the same atomic number butdifferent mass numbers. As is known to those of skill in the art,certain atoms, such as hydrogen occur in different isotopic forms. Forexample, hydrogen includes three isotopic forms, protium, deuterium andtritium. As will be apparent to those of skill in the art uponconsideration of the present compounds, certain compounds can beenriched at a given position with a particular isotope of the atom atthat position. For example, compounds having a fluorine atom, may besynthesized in a form enriched in the radioactive fluorine isotope ¹⁸F.Similarly, compounds may be enriched in the heavy isotopes of hydrogen:deuterium and tritium; and similarly can be enriched in a radioactiveisotope of carbon, such as ¹³C. Such isotopic variant compounds undergodifferent metabolic pathways and can be useful, for example, in studyingthe ubiquitination pathway and its role in disease. Of course, incertain embodiments, the compound has substantially the same isotopiccharacter as naturally-occurring materials.

The compounds of the present disclosure may contain chiral centers,which may be either of the (R) or (S) configuration, or may comprise amixture thereof. Accordingly, the present invention also includesstereoisomers of the compounds described herein, where applicable,either individually or admixed in any proportions. Stereoisomers mayinclude, but are not limited to, enantiomers, diastereomers, racemicmixtures (racemates), and combinations thereof. Such stereoisomers canbe prepared and separated using conventional techniques, either byreacting enantiomeric starting materials, or by separating isomers ofcompounds of the present invention.

Isomers may further include tautomers and geometric isomers. Examples ofgeometric isomers include, but are not limited to, cis isomers or transisomers across a double bond. Other isomers are contemplated among thecompounds of the present disclosure. The isomers may be used either inpure form or in admixture with other isomers of the compounds disclosedherein. In some embodiments, compounds of the present disclosure mayhave a natural CBG-type configuration as indicated below:

One of ordinary skill in the art of chemistry will also appreciate thatthe disclosed structures, unless otherwise indicated are intended toinclude all possible stereoisomers of the claimed molecule, includingmixtures of certain or all stereoisomers. However, compounds drawn withcertain stereochemistry at one or more stereocenters are indicative ofthe compounds in that particular embodiment having the indicatedstereochemistry. Compounds and stereocenters drawn with ambiguousstereochemistry are meant to convey any stereoisomer or mixture thereof,e.g., a racemic mixture of compounds or a purified subset ofstereoisomers.

As used herein, the terms “individual,” “patient,” or “subject”, usedinterchangeably, refer to any animal, including mammals, and preferablyhumans.

As used herein, the phrase “therapeutically effective amount” or“effective amount” refers to the amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsethat is being sought in a cell, tissue, system, animal, individual orhuman by a researcher, veterinarian, medical doctor or other clinician.

In certain embodiments, an effective amount can be an amount suitablefor

-   (i) inhibiting the progression the disease;-   (ii) prophylactic use for example, preventing or limiting    development of a disease, condition or disorder in an individual who    may be predisposed or otherwise at risk to the disease, condition or    disorder but does not yet experience or display the pathology or    symptomatology of the disease;-   (iii) inhibiting the disease; for example, inhibiting a disease,    condition or disorder in an individual who is experiencing or    displaying the pathology or symptomatology of the disease, condition    or disorder;-   (iv) ameliorating the referenced disease state, for example,    ameliorating a disease, condition or disorder in an individual who    is experiencing or displaying the pathology or symptomatology of the    disease, condition or disorder (i.e., reversing or improving the    pathology and/or symptomatology) such as decreasing the severity of    disease; or-   (v) eliciting the referenced biological effect.

As used herein, the terms “treatment” and “treating” means (i)ameliorating the referenced disease state, condition, or disorder (or asymptom thereof), such as, for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing or improving the pathology and/or symptomatology) suchas decreasing the severity of disease or symptom thereof, or inhibitingthe progression of disease; or (ii) eliciting the referenced biologicaleffect (e.g., inducing apoptosis, or inhibiting glutathione synthesis).

As used herein, the terms “preventing” or “prevent” means completely orpartially preclude or delay the onset in a subject of a referenceddisease state, condition, or disorder (or a symptom thereof).

Methods of Preparation

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith and March, March’s Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Fifth Edition,Wiley-Interscience, 2001; or Vogel, A Textbook of Practical OrganicChemistry, Including Qualitative Organic Analysis, Fourth Edition, NewYork: Longman, 1978).

Compounds as described herein can be purified by any of the means knownin the art, including chromatographic means, such as HPLC, preparativethin layer chromatography, flash column chromatography and ion exchangechromatography. Any suitable stationary phase can be used, includingnormal and reversed phases as well as ionic resins. Most typically thedisclosed compounds are purified via silica gel and/or aluminachromatography. See, e.g., Introduction to Modern Liquid Chromatography,2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons,1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, NewYork, 1969. In further embodiments, compounds may be purified bypreparative HPLC.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas J. F. W. McOmie, “Protective Groups in Organic Chemistry,” PlenumPress, London and New York 1973, in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis,” Third edition, Wiley, New York1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer),Academic Press, London and New York 1981, in “Methoden der organischenChemie,” Houben-Weyl, 4.sup.th edition, Vol. 15/l, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide,Proteine,” Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982,and/or in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide andDerivate,” Georg Thieme Verlag, Stuttgart 1974. The protecting groupsmay be removed at a convenient subsequent stage using methods known fromthe art.

A “leaving group” as used herein (e.g. suitable as LG) refers to amoiety of a reactant (e.g., the alkylhalogenide of the disclosure) thatis displaced from the first reactant in the chemical reaction. Acomprehensive and non-limiting list of suitable leaving groups can befound in J. March, Advanced Organic Chemistry, John Wiley and Sons, N.Y.(2013). Examples of suitable leaving groups include, but are not limitedto, halogen (such as Cl or Br), acetoxy, and sulfonyloxy groups (such asmethyl sulfonyloxy, trifluoromethylsulfonyloxy (“triflate”),p-toluenesulfonyloxy (“tosylate”)).

The compounds disclosed herein can be made using procedures familiar tothe person of ordinary skill in the art and as described herein, forexample in Schemes 1 - 3. One of skill in the art can adapt the reactionsequences of schemes and examples as provided herein to fit the desiredtarget molecule. Of course, in certain situations one of skill in theart will use different reagents to affect one or more of the individualsteps or to use protected versions of certain of the substituents.Additionally, one skilled in the art would recognize that compounds ofthe disclosure can be synthesized using different routes altogether. Forexample, the person of ordinary skill in the art may adapt theprocedures described herein and/or other procedures familiar to theperson of ordinary skill in the art to make the compounds describedherein.

wherein R¹, R², R³, and R⁴ are as defined in formula(l).

wherein R¹, R², and R^(4d) are as defined in formula (I).

wherein R¹, R², and R^(4a) are as defined in formula (I).

wherein R^(4d) is as defined in formula (I).

wherein R^(4a) and R^(4c) are as defined in formula (I).

EXAMPLES

The preparation of the compounds of the disclosure is illustratedfurther by the following examples, which are not to be construed in anyway as limiting the disclosure in scope or spirit to the specificprocedures and compounds described in them. These examples are offeredto illustrate the invention.

Compound Synthesis and Formulation

Step a. To a solution of olivetol (10 g, 55.48 mmol) in dry acetone atroom temperature was added K₂CO₃ (23.00 g, 166.44 mmol) and dimethylsulfate (27.99 g, 221.92 mmol). The reaction mixture was stirred at roomtemperature for 15 min and refluxed for 14 h. The reaction mixture wascooled to room temperature, filtered, and the filtrate was concentrated.The crude mixture was diluted in diethyl ether and the organic layer wasstirred with 10% NaOH for 1 h at room temperature. The organic layer wasthen washed with 1 M HCI and water, dried over Na₂SO₄ and concentratedto give 1,3-dimethoxy-5-pentyl-benzene, which was used for next stepswithout further purification.

Step b. To a solution of 1,3-dimethoxy-5-pentyl-benzene (4.0 g, 19.20mmol) and chlorosulfonic acid (11.19 g, 96.02 mmol, 6.39 mL) incyclohexane (12 mL) at 60° C. was added dimethyl carbonate (9.00 g,99.86 mmol, 8.41 mL) dropwise and the temperature was increased to 70°C. The reaction mixture was stirred for 2 h at this temperature and thencooled to room temperature. The mixture was poured into cold water andextracted with diethyl ether. Combined organic layers were dried overNa₂SO₄ and concentrated. The crude mixture was purified by flash columnchromatography using ethyl acetate-hexane to afford2,4-dimethoxy-6-pentyl-benzenesulfonyl chloride as light-yellow oil (49%yield). ¹H NMR (400 MHz, CD₃CN) δ 6.62 (d, J = 2.5 Hz, 1H), 6.55 (d, J =2.5 Hz, 1H), 4.01 (s, 3H), 3.91 (s, 3H), 3.07 - 2.98 (m, 2H), 1.68-1.60(m, 2H), 1.41-1.35 (m, 4H), 0.94 - 0.89 (m, 3H).

Step c. To a 10 mL microwave vial was added2,4-dimethoxy-6-pentyl-benzenesulfonyl chloride (325 mg, 1.06 mmol) anddichloromethane (DCM; 3 mL). The solution was stirred at roomtemperature and Et₃N (221 µL, 1.59 mmol) was added dropwise. The mixturewas stirred for 10 min after which methylamine (2M in methanol 1.06 mL)was added dropwise. The mixture was stirred for another 4 h at roomtemperature. Water was added and the mixture was extracted with DCM. Thecombined organic layers were filtered, concentrated and purified byflash column chromatography using ethyl acetate-hexane to give2,4-dimethoxy-N-methyl-6-pentyl-benzenesulfonamide (62% yield). ¹H NMR(400 MHz, CDCl₃) δ 6.44 (s, 2H), 5.15 (s, 1H), 3.96 (s, 3H), 3.88 (s,3H), 3.11 - 3.03 (m, 2H), 2.62 (s, 3H), 1.66 (m, 2H), 1.49 - 1.33 (m,4H), 0.98 - 0.89 (m, 3H).

Step d. To a solution of2,4-dimethoxy-N-methyl-6-pentyl-benzenesulfonamide (150 mg, 0.50 mmol)in DCM (3 mL) at -78° C. was added with boron tribromide (1 M, 2.49 mL)dropwise. The mixture was stirred at room temperature for 12 h, quenchedwith 1M HCI and extracted with DCM. The organic layer was washed withbrine, dried over Na₂SO₄, concentrated and purified by flash columnchromatography using ethyl acetate-hexane to give2,4-dihydroxy-N-methyl-6-pentyl-benzenesulfonamide (70% yield) as awhite solid. ¹H NMR (400 MHz, CDCI3) δ 10.03 (s, 1H), 6.38 (d, J = 2.7Hz, 1H), 6.32 (d, J = 2.6 Hz, 1H), 5.31 (s, 1H), 4.42 (d, J = 5.9 Hz,1H), 2.89 - 2.81 (m, 2H), 2.67 (d, J = 5.4 Hz, 3H), 1.60 (m, 2H), 1.40(dq, J= 10.9, 3.3 Hz, 4H), 0.96 - 0.91 (m, 3H).

Step e. In a dry and argon-purged round-bottom flask sealed with arubber cork and fitted with a stir bar,2,4-dihydroxy-N-methyl-6-pentyl-benzenesulfonamide (95 mg, 0.35 mmol)was charged followed by the addition of chloroform (3 mL) and anhydrousMgSO₄ (63 mg, 0.52 mmol). The flask was placed in an ice bath and cooledfor 10 min. p-Toluenesulfonic acid monohydrate (6.6 mg, 0.035 mmol) wasadded and the reaction mixture was stirred for 10 min. Geraniol (107 mg,0.70 mmol) was added and the reaction was stirred in an ice bath foradditional 30 min. The reaction was removed from the ice bath and thestirred for 18 h at room temperature. The reaction mixture was quenchedwith sat. NaHCO₃ and the organic layer was washed with saturated NaHCO₃and brine. The organic extract was dried over Na₂SO₄, concentrated andpurified by flash column chromatography using ethyl acetate-hexane togive(E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-methyl-6-pentylbenzenesulfonamide(9% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.30 (s, 1H),6.39 (s, 1H), 5.91 (s, 1H), 5.29 (t, J= 6.9 Hz, 1H), 5.07 (d, J= 7.5 Hz,1H), 4.40 (d, J= 5.7 Hz, 1H), 3.45 (d, J= 7.1 Hz, 2H), 2.87 - 2.79 (m,2H), 2.66 (d, J= 5.4 Hz, 3H), 2.15-2.07 (m, 4H), 1.83 (s, 3H), 1.74 -1.62 (m, 8H), 1.40-1.38 (m, 4H), 0.97 - 0.89 (m, 3H). ESI-MS [M+H]⁺:410.3.

The procedures of Example 1 steps a and b were followed to provide2,4-dimethoxy-6-pentylbenzenesulfonyl chloride.

N-isopropyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide was prepared from2,4-dimethoxy-6-pentyl-benzenesulfonyl chloride using the proceduresdescribed in Example 1, step c, and using isopropyalmine in place ofmethylamine. ¹H NMR (400 MHz, CDCl₃) δ 6.46 - 6.39 (m, 2H), 5.09 (s,1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.43 (s, 1H), 3.12 - 3.03 (m, 2H),1.75 - 1.61 (m, 2H), 1.39 (m, 4H), 1.09 (d, J = 6.5 Hz, 6H), 0.97 - 0.84(m, 3H).

2,4-dihydroxy-N-isopropyl-6-pentyl-benzenesulfonamide was prepared fromN-isopropyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide using theprocedures described in Example 1, step d, and was isolated as a yellowoil (60% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 6.45 - 6.35(m, 1H), 6.31 (d, J = 2.6 Hz, 1H), 5.56 (s, 1H), 4.36 (d, J = 7.8 Hz,1H), 3.45 (m, 1H), 2.89 - 2.81 (m, 2H), 1.68 (m, 2H), 1.39 (m, 4H), 1.13(d, J = 6.5 Hz, 6H), 0.98 - 0.87 (m, 3H).

(E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-isopropyl-6-pentylbenzenesulfonamidewas prepared from 2,4-dihydroxy-N-isopropyl-6-pentyl-benzenesulfonamideusing the procedures described in Example 1, step e, and was isolated asa white solid (3% yield). ¹H NMR (400 MHz, CD₃CN) δ 6.25 (s, 1H), 5.04 -5.01 (m, 1H), 5.95 - 4.92 (m, 1H), 3.27-3.21 (3H, m), 2.79-2.74 (m, 2H),2.05-1.99 (4H, m), 1.71 (s, 3H), 1.67-1.47 (m, 8H), 1.40 - 1.29 (m, 4H),1.03 (d, J = 6.4 Hz, 6H), 0.94 (t, J = 7.0 Hz, 3H). ESI-MS [M+H]+:438.3.

The procedures of Example 1 steps a and b were followed to provide2,4-dimethoxy-6-pentylbenzenesulfonyl chloride.

N-cyclohexyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide was prepared from2,4-dimethoxy-6-pentyl-benzenesulfonyl chloride using the proceduresdescribed in Example 1, step c, and using cyclohexylamine in place ofmethylamine (white solid, 62% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.46 -6.37 (m, 2H), 5.20 (d, J = 7.2 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.16(m, 1H), 3.11 - 3.04 (m, 2H), 1.76 - 1.14 (m, 16), 0.93 (m, 3H).

N-cyclohexyl-2,4-dihydroxy-6-pentyl-benzenesulfonamide was prepared fromN-cyclohexyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide using theprocedures described in Example 1, step d, and was isolated as a yellowoil (61% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 6.38 (d, J =2.6 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H), 5.44 (s, 1H), 4.44 (d, J = 7.9Hz, 1H), 3.16-3.10 (1H, m), 2.90-2.82 (m, 2H), 1.80-1.14 (m, 16H),0.98 - 0.91 (m, 3H).

(E)-N-cyclohexyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamidewas prepared from N-cyclohexyl-2,4-dihydroxy-6-pentyl-benzenesulfonamideusing the procedures described in Example 1, step e, and was isolated asa yellowish liquid (8% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H),6.35 (s, 1H), 5.84 (s, 1H), 5.27-5.24 (m, 1H), 5.07-5.04 (m, 1H), 4.40(d, J= 7.9 Hz, 1H), 3.43 (d, J= 7.1 Hz, 2H), 3.14-3.05 (m, 1H), 2.83 -2.79 (m, 2H), 2.11 - 2.04 (m, 4H), 1.80 (s, 3H), 1.78 -1.11 (m, 22H),0.92 - 0.89 (m, 3H). ESI-MS [M+H]⁺: 478.3.

The procedures of Example 1 steps a and b were followed to provide2,4-dimethoxy-6-pentylbenzenesulfonyl chloride.

2,4-dimethoxy-6-pentyl-N-phenyl-benzenesulfonamide was prepared from2,4-dimethoxy-6-pentyl-benzenesulfonyl chloride using the proceduresdescribe in Example 1, step c, and using aniline in place of methylamine(white solid, 52% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.26 - 7.15 (m, 3H),7.13 - 7.07 (m, 2H), 6.42 (d, J= 2.4 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H),4.05 (s, 3H), 3.82 (s, 3H), 2.99 - 2.86 (m, 2H), 1.39 (s, 2H), 1.31 -1.27 (m, 4H), 0.91 - 0.84 (m, 3H).

2,4-dihydroxy-6-pentyl-N-phenyl-benzenesulfonamide was prepared from2,4-dimethoxy-6-pentyl-N-phenyl-benzenesulfonamide using the proceduresdescribed in Example 1, step d, and was isolated as a yellow oil (60%yield). ¹H NMR (400 MHz, CDCl₃) δ 9.79 (s, 1H), 7.32 - 7.26 (m, 2H),7.18 (t, J= 7.4 Hz, 1H), 6.99 (dd, J = 7.4, 1.6 Hz, 2H), 6.57 (s, 1H),6.34 (d, J = 2.6 Hz, 1H), 6.26 (d, J = 2.6 Hz, 1H), 5.34 (s, 1H), 2.88 -2.82 (m, 2H), 1.68 - 1.62 (m, 2H), 1.39 (dq, J = 6.7, 3.3 Hz, 4H), 0.93(t, J = 7.0 Hz, 3H).

(E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-phenylbenzenesulfonamidewas prepared from 2,4-dihydroxy-6-pentyl-N-phenyl-benzenesulfonamideusing the procedures described in Example 1, step e, and was isolated asa yellowish liquid (14% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H),7.29 - 7.25 (m, 2H), 7.19 - 7.13 (m, 1H), 7.00 - 6.95 (m, 2H), 6.63 (s,1H), 6.34 (s, 1H), 5.88 (s, 1H), 5.23 -5.18 (m, 1H), 5.09-5.06 (m, 1H),3.39 (d, J = 7.1 Hz, 2H), 2.85-2.81 (m, 2H), 2.15 - 2.05 (m, 4H), 1.79(s, 3H), 1.70 (s, 3H), 1.62-1.58 (m, 5H), 1.41 - 1.32 (m, 4H), 0.94 -0.90 (m, 3H). ESI-MS [M+H]⁺ : 472.3.

The procedures of Example 1 steps a and b were followed to provide2,4-dimethoxy-6-pentylbenzenesulfonyl chloride.

N-cyclobutyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide was prepared from2,4-dimethoxy-6-pentylbenzenesulfonyl chloride using the proceduresdescribed in Example 1, step c, and using cyclobytylamine in place ofmethylamine (white solid, 90% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.42 (d,J = 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 5.45 (d, J = 9.2 Hz, 1H),3.97 (s, 3H), 3.85 (s, 3H), 3.81-3.76 (m, 1H), 3.10 - 3.02 (m, 2H),2.05-2.03 (m, 2H), 1.79-1.52 (m, 6H), 1.40-1.37 (m, 4H), 0.92 (t, J =6.9 Hz, 3H). ESI-MS [M-H]⁻: 340.20.

N-cyclobutyl-2,4-dihydroxy-6-pentyl-benzenesulfonamide was prepared fromN-cyclobutyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide using theprocedures described in Example 1, step d, and was isolated as atransparent oil (63% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.01 (s, 1H),7.56 (s, 1H), 6.37 (d, J= 2.5 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 5.15(d, J= 8.7 Hz, 1H), 3.71-3.65 (m, 1H), 2.85 - 2.76 (m, 2H), 2.16-2.09(m, 2H), 1.93 - 1.78 (m, 2H), 1.72 - 1.51 (m, 4H), 1.36 - 1.34 (m, 4H),0.89 (t, J = 7.0 Hz, 3H). ESI-MS [M+H]⁺: 314.20.

(E)-N-cyclobutyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamidewas prepared from N-cyclobutyl-2,4-dihydroxy-6-pentylbenzenesulfonamideusing the procedures described in Example 1, step e, and was isolated asa white solid (3% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.29 (s, 1H), 6.36(s, 1H), 5.88 (s, 1H), 5.27 (t, J= 7.1 Hz, 1H), 5.08 (t, J= 7.4 Hz, 1H),4.67 (d, J = 6.2 Hz, 1H), 3.79 - 3.66 (m, 1H), 3.45 (d, J= 7.1 Hz, 2H),2.85 - 2.77 (m, 2H), 2.21 - 2.06 (m, 4H), 1.80-1.66 (m, 15H), 1.40 -1.39 (m, 6H), 0.93 (t, J= 7.0 Hz, 3H). ESI-MS [M-H]⁻: 448.30.

The procedures of Example 1 steps a and b were followed to provide2,4-dimethoxy-6-pentylbenzenesulfonyl chloride.

N-hexyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide was prepared from2,4-dimethoxy-6-pentylbenzenesulfonyl chloride using the proceduresdescribed in Example 1, step c, and using hexylamine in place ofmethylamine (transparent oil, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ6.43-6.41 (m, 2H), 5.19 (t, J= 6.2 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H),3.11 -3.02 (m, 2H), 2.88 (q, J= 6.8 Hz, 2H), 1.72- 1.58 (m, 2H), 1.57 -1.42 (m, 2H), 1.42 - 1.18 (m, 10H), 0.93-0.85 (m, 6H). ESI-MS [M+H]⁺:372.28.

N-hexyl-2,4-dihydroxy-6-pentyl-benzenesulfonamide was prepared fromN-hexyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide using the proceduresdescribed in Example 1, step d, and was isolated as a yellow oil (76%yield). ¹H NMR (400 MHz, CDCl₃) δ 10.06 (s, 1H), 6.38 (d, J = 2.6 Hz,1H), 6.31 (d, J = 2.6 Hz, 1H), 5.48 (s, 1H), 4.43 (s, 1H), 2.94 (q, J =6.8 Hz, 2H), 2.88 - 2.83 (m, 2H), 1.72 - 1.60 (m, 4H), 1.53 - 1.24 (m,10H), 0.95-0.86 (m, 6H). ESI-MS [M-H]⁻: 342.20.

(E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-N-hexyl-2,4-dihydroxy-6-pentylbenzenesulfonamidewas prepared from N-hexyl-2,4-dihydroxy-6-pentylbenzenesulfonamide usingthe procedures described in Example 1, step e, and was isolated as awhite solid (5.5% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.33 (s, 1H), 6.37(s, 1H), 5.94 (s, 1H), 5.27 (t, J= 6.6 Hz, 1H), 5.10-5.06 (m, 1H),4.46-4.42 (m, 1H), 3.44 (d, J= 7.1 Hz, 2H), 2.97-2.81 (m, 4H), 2.14 -2.07 (m, 4H), 1.82 (s, 3H), 1.70 (s, 3H), 1.61 (s, 3H), 1.72-1.63 (2H,m), 1.49-1.23 (m, 12H), 0.95-0.86 (m, 6H). ESI-MS [M+H]⁺:480.40.

The procedures of Example 1 steps a and b were followed to provide2,4-dimethoxy-6-pentylbenzenesulfonyl chloride.

N-allyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide was prepared from2,4-dimethoxy-6-pentylbenzenesulfonyl chloride using the proceduresdescribed in Example 1, step c, and using allylamine in place ofmethylamine (white solid, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.41 (d,J = 2.4 Hz, 1H), 6.39 (d, J= 2.4 Hz, 1H), 5.77-5.67 (m, 1H), 5.33 -5.26(m, 1H), 5.18-5.13 (m, 1H), 5.08 - 5.04 (m, 1H), 3.92 (s, 3H), 3.84 (s,3H), 3.52 (t, J = 6.1 Hz, 2H), 3.07 - 2.98 (m, 2H), 1.67-1.59 (m, 2H),1.35-1.34 (m, 4H), 0.88 (t, J= 7.0 Hz, 3H). ESI-MS [M-H]⁻: 326.20.

N-allyl-2,4-dihydroxy-6-pentyl-benzenesulfonamide was prepared fromN-allyl-2,4-dimethoxy-6-pentyl-benzenesulfonamide using the proceduresdescribed in Example 1, step d, and was isolated as a yellow oil (92%yield). ¹H NMR (400 MHz, CDCl₃) δ 9.98 (s, 1H), 7.15 (s, 1H), 6.39 (d, J= 2.6 Hz, 1H), 6.32 (d, J = 2.6 Hz, 1H), 5.79-5.71 (m, 1H), 5.21 (d, J =18.1 Hz, 1H), 5.14 (d, J= 12.4 Hz, 1H), 4.75 (s, 1H), 3.57 (t, J= 5.8Hz, 2H), 2.90 -2.79 (m, 2H), 1.71 - 1.59 (m, 2H), 1.38 (m, 4H), 0.91 (t,J= 5.9 Hz, 3H). ESI-MS [M+H]⁺: 300.20.

(E)-N-allyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamidewas prepared from N-allyl-2,4-dihydroxy-6-pentylbenzenesulfonamide usingthe procedures described in Example 1, step e, and was isolated as awhite solid (6.1 % yield). ¹H NMR (400 MHz, CDCl₃) δ 10.28 (s, 1H), 6.37(s, 1H), 5.91 (s, 1H), 5.80-5.70 (m, 1H), 5.29-5.06 (m, 4H), 4.52 (t, J=5.7 Hz, 1H), 3.61 - 3.56 (m, 2H), 3.44 (d, J= 7.1 Hz, 2H), 2.92 - 2.82(m, 2H), 2.14 - 2.07 (m, 4H), 1.83 (s, 3H), 1.72 - 1.52 (m, 8H), 1.45 -1.37 (m, 4H), 0.96 - 0.90 (m, 3H). ESI-MS [M+H]⁺: 436.30.

The procedures of Example 1 steps a and b were followed to provide2,4-dimethoxy-6-pentylbenzenesulfonyl chloride.

4-(2,4-dimethoxy-6-pentyl-phenyl)sulfonylmorpholine was prepared from2,4-dimethoxy-6-pentylbenzenesulfonyl chloride using the proceduresdescribed in Example 1, step c, and using morpholine in place ofmethylamine (white solid, 90% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.41 (d,J = 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H),3.79 - 3.70 (m, 4H), 3.34 - 3.24 (m, 4H), 3.07 - 2.98 (m, 2H), 1.72 -1.61 (m, 2H), 1.47 -1.32 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H).ESI-MS[M+H]⁺: 358.20.

4-morpholinosulfonyl-5-pentyl-benzene-1,3-diol was prepared from4-(2,4-dimethoxy-6-pentyl-phenyl)sulfonylmorpholine using the proceduresdescribed in Example 1, step d, and was isolated as a yellow oil (13%yield). ¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 6.39 (d, J= 2.6 Hz, 1H),6.31 (d, J= 2.6 Hz, 1H), 6.18 (s, 1H), 3.80 - 3.71 (m, 4H), 3.22 - 3.16(m, 4H), 2.88 - 2.81 (m, 2H), 1.69 - 1.59 (m, 2H), 1.39-1.37 (m, 4H),0.93 (t, J = 7.0 Hz, 3H). ESI-MS [M+H]⁺: 330.197.

(E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(morpholinosulfonyl)-5-pentylbenzene-1,3-diolwas prepared from 4-morpholinosulfonyl-5-pentyl-benzene-1,3-diol usingthe procedures described in Example 1, step e, and was isolated as awhite solid (9% yield). ¹H NMR (400 MHz, CDCl₃) 8 10.29 (s, 1H), 6.39(s, 1H), 5.94 (s, 1H), 5.28 (t, J= 6.8 Hz, 1H), 5.08 (t, J= 7.1 Hz, 1H),3.77 - 3.72 (m, 4H), 3.44 (d, J= 7.2 Hz, 2H), 3.21 - 3.14 (m, 4H),2.86 - 2.79 (m, 2H), 2.20 - 2.05 (m, 4H), 1.83 (s, 3H), 179 - 1.61 (m,8H), 1.42 - 1.34 (m, 4H), 0.94 (t, J = 6.9 Hz, 3H). ESI-MS [M+H]⁺:466.30.

To a stirred solution of(E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzoicacid (cannabigerolic acid; 400 mg, 1.11 mmol) and4-Dimethylaminopyridine (DMAP; 6.8 mg, 0.055 mmol) in tetrahydrofuran(THF; 5 mL) under N₂ was added triethylamine (773 µL, 5.55 mmol),followed by acetic anhydride (230 µL, 2.44 mmol) dropwise. Afterstirring at room temperature for 1 h, the mixture was quenched withwater and extracted with ethyl acetate. The organic extract was washedwith brine, followed by water and 1N HCl. The organic phase was driedover Na₂SO₄, filtered and concentrated. The crude mixture was purifiedby flash column chromatography on silica gel (ethyl acetate -hexane) togive(E)-2,4-diacetoxy-3-(3,7-dimethylocta-2,6-dien-1-yl)-6-pentylbenzoicacid (63% yield). ¹H NMR (400 MHz, CD₃CN) δ 6.97 (s, 1H), 5.11-5.07 (m,1H), 5.01-4.98 (m, 1H), 3.16 (d, J= 7.7 Hz, 2H), 2.73 - 2.65 (m, 2H),2.28 (s, 3H), 2.24 (s, 3H), 2.09-2.02 (m, 2H), 2.00-1.95 (m, 2H), 1.73(s, 3H), 1.66 (s, 3H), 1.60 (m, 5H), 1.41 -1.27 (m, 4H), 0.96 -0.87 (m,3H). ESI-MS [M-H]⁻ 443.3.

To a stirred solution of benzenesulfonamide (177 mg, 1.12 mmol) indimethylformamide (DMF; 5 mL) under N₂ was added sodium hydride (27 mg,1.12 mmol) portion-wise. Meanwhile a solution of(E)-2,4-diacetoxy-3-(3,7-dimethylocta-2,6-dien-1-yl)-6-pentylbenzoicacid (100 mg, 0.225 mmol) and 1-hydroxybenzotriazole hydrate (52 mg,0.34 mmol) in DMF (2 mL) under N₂ was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 65 mg, 0.34 mmol)and the mixture was stirred at room temperature for 2 h. The solution ofthe activated acid was added to the suspension of the sulfonamide anionslowly and the mixture was stirred for 1 h. The mixture was quenchedwith water and extracted with ethyl acetate. The organic extract waswashed with brine, followed by water and 1N HCl. The organic phase wasdried, filtered and concentrated. The crude mixture was purified byflash column chromatography on silica gel (ethyl acetate -hexane) togive(E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-((phenylsulfonyl)carbamoyl)-1,3-phenylene diacetate (9.1 % yield). ESI-MS [M-H]⁻ 582.3.

To a stirred solution of(E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-((phenylsulfonyl)carbamoyl)-1,3-phenylenediacetate (12 mg, 0.021 mmol) in methanol (0.5 mL) was added a solutionof lithium hydroxide monohydrate (4.3 mg, 0.10 mmol) in H₂O (0.1 mL).THF (0.5 mL) was added to aid solubility. The resulting mixture wasstirred at room temperature overnight. The mixture was diluted withwater, neutralized with 1N HCl and extracted with DCM. The organic phasewas dried over Na₂SO₄, filtered and concentrated. The crude mixture waspurified by flash column chromatography on silica gel (ethyl acetate-hexane) to give (E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(phenylsulfonyl)benzamide(4% yield).

(E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyridin-3-ylsulfonyl)benzamidewas prepared as described in Example 9, using pyridine-3-sulfonamide inplace of benzenesulfonamide (12% yield). ¹H NMR (400 MHz, CD₃CN) δ 9.19(s, 1H), 8.87 (d, J= 4.9 Hz, 1H), 8.40-8.37 (m, 1H), 7.61 (dd, J= 8.1,4.8 Hz, 1H), 7.24 (s, 1H), 6.28 (s, 1H), 5.14-5.07 (m, 2H), 3.26 (d, J=7.0 Hz, 2H), 2.52-2.48 (m, 2H), 2.13-2.00 (m, 4H), 1.76 (s, 3H), 1.64(s, 3H), 1.593 (s, 3H), 1.39-1.15 (m, 6H), 0.88 (t, J= 7.2 Hz, 3H).ESI-MS [M-H]⁻ = 499.3.

2,4-dimethoxy-6-pentyl-benzenesulfonyl chloride (1.00 g, 3.26 mmol) wasadded to a solution of sodium sulfite (1.63 g, 12.93 mmol) and sodiumbicarbonate (1.09 g, 12.98 mmol) in H₂O (16 mL) at room temperature. Thereaction mixture was stirred at 70° C. for 12 h and solvent wasevaporated under reduced pressure. The resulting solid was suspended inethanol (10 mL) and stirred for 20 min at room temperature. The mixturewas filtered and the filtrate was concentrated to give sodium2,4-dimethoxy-6-pentylbenzenesulfinate (892 mg, 3.03 mmol, 93% yield) asa white solid: ¹H NMR (400 MHz, CDCl₃) δ 6.17 (d, J= 2.3 Hz, 1H), 6.11(d, J= 2.3 Hz, 1H), 3.75 (s, 3H), 3.54 (s, 3H), 2.78 (t, J= 7.9 Hz, 2H),1.59 (m, 2H), 1.33 - 1.22 (m, 4H), 0.97 - 0.82 (m, 3H).

In a 10 mL microwave vial was added sodium2,4-dimethoxy-6-pentylbenzenesulfinate (200 mg, 0.68 mmol) and dry DMF(3 mL) under argon atmosphere. The solution was stirred at roomtemperature and iodomethane (85 µL, 1.36 mmol) was added dropwise. Themixture was stirred at 80° C. for 12 h. Water was added, and the mixturewas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated and purified by flashcolumn chromatography using ethyl acetate - hexane to give1,5-dimethoxy-2-methylsulfonyl-3-pentyl-benzene (187 mg, 0.65 mmol, 96%yield) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 6.44 (s, 1H), 6.39 (s,1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.23 (s, 3H), 3.11-3.06 (m, 2H),1.66-1.62 (m, 2H), 1.39-1.32 (m, 4H), 0.92 - 0.89 (m, 3H). ESI-MS[M+H]⁺: 287.1.

To a solution of 1,5-dimethoxy-2-methylsulfonyl-3-pentyl-benzene (187mg, 0.62 mmol) in DCM (3 mL) at -78° C. was added boron tribromide (1 M,3.08 mL) dropwise. The mixture was stirred at room temperature for 12 h,quenched with 1M HCl and extracted with DCM. The organic layer waswashed with brine, dried over Na₂SO₄, concentrated and purified by flashcolumn chromatography using ethyl acetate - hexane to give4-methylsulfonyl-5-pentyl-benzene-1,3-diol (101 mg, 0.39 mmol, 63%yield) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 10.01 (s, 1H), 7.06 (s,1H), 6.36 (d, J = 2.7 Hz, 1H), 6.30 (d, J = 2.6 Hz, 1H), 3.14 (s, 3H),2.84 - 2.80 (m, 2H), 1.65-1.61 (m, 2H), 1.38-1.32 (m, 4H), 0.90-0.85 (m,3H). ESI-MS [M-H]⁻ : 257.1.

In a dry and argon-purged round-bottom flask sealed with a rubber corkand fitted with a stir bar, 4-methylsulfonyl-5-pentyl-benzene-1,3-diol(100 mg, 0.39 mmol) was charged followed by the addition of chloroform(3 mL) and anhydrous MgSO₄ (140 mg, 1.16 mmol). The flask was placed inan ice bath and cooled for 10 min. p-Toluenesulfonic acid monohydrate(7.4 mg, 0.039 mmol) was added and the reaction mixture was stirred for10 min. Geraniol (119 mg, 0.77 mmol) was added and the reaction wasstirred in an ice bath for additional 30 min. After stirring at roomtemperature for 18 h, the reaction mixture was quenched with sat. NaHCO₃and the organic layer was washed with sat. NaHCO₃ and brine. The organicextract was dried over Na₂SO₄, concentrated and purified by C18 reversephase chromatography (CH₃CN—H₂O) to give(E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(methylsulfonyl)-5-pentylbenzene-1,3-diol(2% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 6.35 (s,1H), 5.90 (s, 1H), 5.27 (t, J = 6.7 Hz, 1H), 5.06-5.03 (m, 1H), 3.41 (d,J = 7.1 Hz, 2H), 3.14 (s, 3H), 2.84-2.80 (m, 2H), 2.12-2.05 (m, 4H),1.80 (s, 3H), 1.76 - 1.59 (m, 8H), 1.40-1.34 (m, 4H), 0.90 (t, J = 7.0Hz, 3H). ESI-MS [M-H]⁻: 393.2.

To a dried 25 mL round-bottom flask, charged with2,4-dimethoxy-6-pentyl-benzenesulfonyl chloride (350 mg, 1.14 mmol) inDCM (6 mL) was added phenol (128.83 mg, 1.37 mmol). To the resultingsolution was added dropwise a solution of 1,4-diazabicyclo[2.2. 2]octane(DABCO; 128 mg, 1.14 mmol) in DCM (3 mL). The reaction was stirred atroom temperature for 2 h and monitored by TLC. The reaction mixture wasthen quenched with 0.1 N HCl and extracted with DCM. The organic layerswere combined, dried over Na₂SO₄, filtered and concentrated. The crudewas purified by flash column chromatography on silica gel (ethylacetate - hexane) to yield phenyl 2,4-dimethoxy-6-pentylbenzenesulfonateas a clear oil (304 mg, 73% yield).

To a microwave vial charged with phenyl2,4-dimethoxy-6-pentylbenzenesulfonate (301 mg, 0.825 mmol) in DCM (1.5mL) was added boron tribromide (1M, 2.06 mL) dropwise. The resultingmixture was stirred at room temperature for 12 h and quenched with aq.NaHCO₃. The mixture was diluted with NaOH 1N and extracted with both DCMand ethyl acetate. The aqueous phase was then acidified using 1M HCl andextracted with DCM and ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theobtained crude was purified via flash column chromatography on silicagel (ethyl acetate - hexane) to yield phenyl2,4-dihydroxy-6-pentylbenzenesulfonate (201 mg, 72% yield). ¹H NMR (400MHz, CDCl₃) δ 7.31 - 7.26 (m, 3H), 7.01 - 6.99 (m, 2H), 6.43-6.42 (m,1H), 6.21 - 6.20 (m, 1H), 2.98-2.94 (m, 2H), 1.72 - 1.64 (m, 2H), 1.45 -1.33 (m, 4H), 0.91 (t, J= 7.0 Hz, 3H).

To a dried microwave vial purged with argon and charged with phenyl2,4-dihydroxy-6-pentyl-benzenesulfonate (200 mg, 0.59 mmol) in anhydrouschloroform (2.5 mL) was added magnesium sulfate (286 mg, 2.38 mmol),followed by p-toluenesulfonic acid monohydrate (11 mg, 0.059 mmol). Thereaction mixture was cooled to 0° C. and stirred for 10 min. Geraniol(183 mg, 1.19 mmol) was added dropwise and the resulting mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith aq. NaHCO₃ and extracted with DCM. The organic extract was driedover Na₂SO₄, filtered and concentrated. The crude mixture was purifiedby flash column chromatography on silica gel (ethyl acetate - hexane),followed by C18 reverse phase chromatography (CH₃CN—H₂O) to yieldphenyl-(E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonateas a clear oil (6.5% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.46 (s, 1H),7.36 - 7.29 (m, 3H), 7.05 - 7.01 (m, 2H), 6.44 (s, 1H), 5.99 (s, 1H),5.21 - 5.12 (m, 1H), 5.12 - 5.04 (m, 1H), 3.35 (d, J= 7.1 Hz, 2H),2.99 - 2.92 (m, 2H), 2.09 (m, 4H), 1.78 (s, 3H), 1.74 - 1.62 (m, 8H),1.47 - 1.33 (m, 4H), 0.93 (t, J= 7.0 Hz, 3H). ESI-MS [M-H]⁻: 471.24.

Example 13

The following compounds may be prepared according to the proceduresknown to those of skill in the art in view of Schemes 1 - 6 and Examples1-12:

Comp. No. Name Structure 13-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonicacid

2 sodium3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonate

44-(cyclopropylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

54-(tert-butylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

64-(benzylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

72-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(phenylsulfonyl)benzene-1,3-diol

82-(3,7-dimethylocta-2,6-dien-1-yl)-4-((4-nitrophenyl)sulfonyl)-5-pentylbenzene-1,3-diol

92-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyridin-3-ylsulfonyl)benzene-1,3-diol

102-(3,7-dimethylocta-2,6-dien-1-yl)-4-(furan-3-ylsulfonyl)-5-pentylbenzene-1,3-diol

11 4-((1H-imidazol-4-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

122-(3,7-dimethylocta-2,6-dien-1-yl)-4-(oxetan-3-ylsulfonyl)-5-pentylbenzene-1,3-diol

132-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-((perfluorophenyl)sulfonyl)benzene-1,3-diol

144-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)cyclohexan-1-one

151-(2-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)ethyl)pyrrolidine-2,5-dione

164-((2-(dimethylamino)ethyl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

171-(3-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)piperidin-1-yl)ethan-1-one

184-((2-chloropyrimidin-5-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

193-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide

213-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N,N-dimethyl-6-pentylbenzenesulfonamide

22N-cyclopropyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide

25N-benzyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide

262-(3,7-dimethylocta-2,6-dien-1-yl)-4-((4-methylpiperazin-1-yl)sulfonyl)-5-pentylbenzene-1,3-diol

272-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(piperidin-1-ylsulfonyl)benzene-1,3-diol

293-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyridin-3-yl)benzenesulfonamide

303-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyrimidin-2-yl)benzenesulfonamide

313-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-(2-oxopropyl)-6-pentylbenzenesulfonamide

321-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)azetidin-3-one

333-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-(oxetan-2-ylmethyl)-6-pentylbenzenesulfonamide

344-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

354-((2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol

36((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)alanine

37 methyl((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)alaninate

38N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-morpholinopropanamide

394-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonamido)-4-oxobutanoicacid

40N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-(4-methylpiperazin-1 -yl)propanamide

412-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide

42N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(2-methoxyethoxy)acetamide

432-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-hydroxypropanamide

442-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)propanamide

453-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-methylpropanamide

46N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide

47N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-oxobutanamide

48N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(3-methyl-1H-1 ,2,4-triazol-5-yl)acetamide

49N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-1H-1,2,4-triazole-5-carboxamide

50N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)oxetane-2-carboxamide

51N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)benzamide

52N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)nicotinamide

53N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-phenylacetamide

54N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(furan-2-yl)acetamide

55N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(oxazol-2-yl)acetamide

56N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(thiazol-2-yl)acetamide

57 2-(1H-benzo[d]imidazol-2-yl)-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide

59N-(cyclohexylsulfonyl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzamide

603-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-((prop-1-en-1-yl)sulfonyl)benzamide

61 N-((1H-benzo[d]imidazol-2-yl)sulfonyl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzamide

The disclosure also provides analogs of compounds disclosed herein,including for example analogs of compounds 19, 20, 22-25, 29-31, 33, and36-66 in which the amino moiety in sulfonamide is methylated. Forexample, such an analog of compound 61 isN-((1H-benzo[d]imidazol-2-yl)sulfonyl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-methyl-6-pentylbenzamide;such analogs of all other compounds of the Table are specificallycontemplated where chemically reasonable.

Radioligand Competitive Binding Assays - CB1 and CB2 Example 14

Compounds of the present disclosure were tested for CB1 receptor bindingaffinity and for CB2 receptor binding affinity. As used herein, “bindingaffinity” is represented by the IC₅₀ value, which was experimentallydetermined as described herein. The lower the IC₅₀ value the higher thebinding affinity. A compound of the present disclosure may be said tohave “binding selectivity” if it has a higher binding affinity for onereceptor compared to the other. For example, a compound that has an IC₅₀of 1 µM for CB1 and 0.1 µM for CB2 is 10 times more selective for theCB2 receptor.

CB1 Membrane Preparation

The membranes were prepared from CHO-K1 (Chinese hamster ovary) cellsstably transfected with the human CB1 receptor (Cat.# ES-110-C; PerkinElmer, Boston, MA). The cells were grown adherently and maintained inHam’s F12 medium containing 10% fetal bovine serum (FBS), penicillin,streptomycin and geneticin (G418) at 37° C. in a humid atmosphere of 5%CO₂ following the manufacturer’s instructions.

For membrane preparation the cells were washed with PBS and scraped offthe plates in cold homogenization buffer (25 mM HEPES (pH 7.4), 2 mMEDTA) containing protease inhibitor cocktail (Sigma Cat.# P8340). Thecell suspension was homogenized with a Pro-PK-01200D PolytronHomogenizer (Pro Scientific) and then centrifuged for 30 min at 120,000× g. The supernatant was discarded and the pellet was re-suspended inthe homogenization buffer and stored at -80° C. until the time of use.

CB1 Radioligand Binding Assay

CP 55,940 is a synthetic cannabinoid that mimics the effects ofnaturally occurring THC. It acts as a full agonist at both cannabinoidCB1 and CB2 receptors. Radiolabeled ligands represent one of the mostsensitive methods for probing receptor binding biology. In thisexperiment, 3H radiolabeled CP 55,940, i.e. [3H]CP 55,940 (Perkin Elmer,Boston, MA), was used as a radioligand for the CB1 receptor.

[3H]CP 55,940 displacement assays were used for the determination of thebinding affinity of compounds for the CB1 receptor (Scheme 7; below).

Scheme 7: Schematic representation of the radioligand binding assay forCB1 and CB2

The competition binding experiments (single dose and dose-response) wereperformed by incubating 0.8 nM of [3H]CP 55,940 (specific activity 101Ci/mmol, Perkin Elmer) and different concentrations of compoundsdisclosed herein with membranes prepared as above from CHO—K1 cellsexpressing human CB1 receptor (6 µg of protein/well), 50 mM Tris-HCl (pH7.4), 5 mM MgCl₂, 1 mM CaCl₂, and 2 mg/mL BSA.

For the single dose experiments, the compound stocks (usually 10 mM inDMSO) were diluted to working stocks in the binding buffer to give thefinal compound concentrations of 10 µM and 1 µM. For the dose-responseexperiments, the test compounds were sequentially diluted to provide thedesired concentration range for the IC₅₀ determination. In each case thecompounds were pre-incubated with the membrane for 20 min, before addingthe radioligand.

After incubation with the radioligand for 60 min at 37° C., theincubation was terminated by rapid filtration of the assay mixturethrough MultiScreen®_(HTS) ⁺ 96-well filter plates (Millipore, Cat.#MSFCNXB), pre-soaked for 60 min with 50 mM Tris-HCl (pH 7.4) containing0.33% polyethylenimine (PEI). The nonspecific binding (NSB) wasdetermined in the presence of 10 µM unlabelled CP 55,940. After dryingthe filter plate at 50° C. for at least 60 min, the filter-boundradioactivity was determined by scintillation spectrometry using the1450 MicroBeta Plate Counter (Perkin Elmer, Boston, MA). From thedose-response experiments, the IC₅₀ values were determined (see Table 1,CB1 IC₅₀).

In Table 1 below, the fold difference in selectivity between CB1 and CB2binding is indicated, with the fold difference presented in the columnof the receptor that exhibited the higher binding affinity (i.e. CB1 orCB2). Where the test compound had about the same affinity for bothreceptors, this is represented by a value of 1.00 in the column for bothreceptors. None of the compounds listed in Table 1 were found to exhibitselectivity for the CB1 receptor.

CB2 Membrane Preparation

The membranes were prepared from CHO-K1 (Chinese hamster ovary) cellsstably transfected with the human CB2 receptor (Cat.# ES-111-C; PerkinElmer, Boston, MA). The cells were grown adherently and maintained inHam’s F12 medium containing 10% fetal bovine serum (FBS), penicillin,streptomycin and geneticin (G418) at 37° C. in a humid atmosphere of 5%CO₂ following the manufacturer’s instructions.

For membrane preparation the cells were washed with PBS and scraped offthe plates in cold homogenization buffer (25 mM HEPES (pH 7.4), 2 mMEDTA) containing protease inhibitor cocktail (Sigma Cat.# P8340). Thecell suspension was homogenized with a Pro-PK-01200D PolytronHomogenizer (Pro Scientific) and then centrifuged for 30 min at 120,000× g. The supernatant was discarded and the pellet was re-suspended inthe homogenization buffer and stored at -80° C. until the time of use.

CB2 Radioligand Binding Assay

In this experiment, 3H radiolabeled CP 55,940, i.e. [3H]CP 55,940(Perkin Elmer, Boston, MA), was used as a radioligand for the CB2receptor to determine the binding affinity of compounds for the CB2receptor (Scheme 7; above).

The competition binding experiments (single dose and dose-response) wereperformed by incubating 0.6 nM of [3H]CP55,940 (specific activity 101Ci/mmol, Perkin Elmer) and different concentrations of compoundsdisclosed herein with membranes prepared as above from CHO—K1 cellsexpressing human CB2 receptor (1 µg of protein/well), 50 mM Tris-HCl (pH7.4), 5 mM MgCl₂, 1 mM CaCl₂, and 2 mg/mL BSA.

For the single dose experiments, the compound stocks (usually 10 mM inDMSO) were diluted to working stocks in the binding buffer to give thefinal compound concentrations of 10 µM and 1 µM. For the dose-responseexperiments the test compounds were sequentially diluted to provide thedesired concentration range for the IC50 determination. In each case thecompounds were pre-incubated with the membrane for 20 min, before addingthe radioligand.

After incubation with the radioligand for 60 min at 37° C., theincubation was terminated by rapid filtration of assay mixture throughMultiScreen®_(HTS) ⁺ 96-well filter plates (Millipore, Cat.# MSFCNXB),pre-soaked for 60 min with 50 mM Tris-HCl (pH 7.4) containing 0.33 %polyethylenimine (PEI). The nonspecific binding (NSB) was determined inthe presence of 10 µM unlabelled CP55,940. After drying the filter plateat 50° C. for at least 60 min, the filter-bound radioactivity wasdetermined by scintillation spectrometry using the 1450 MicroBeta PlateCounter (Perkin Elmer, Boston, MA). From the dose-response experiments,the IC₅₀ values were determined (see Table 1, CB2 IC₅₀).

Compounds of the present disclosure listed in Table 1 exhibitedselectivity for the CB2 receptor over the CB1 receptor. Again, in Table1 below, the fold difference in selectivity between CB1 and CB2 bindingis indicated, with the fold difference presented in the column of thereceptor that exhibited the higher binding affinity (i.e. CB1 or CB2).Where the test compound had about the same affinity for both receptors,this is represented by a value of 1.00 in the column for both receptors.

TABLE 1 Data from Radioligand Competitive Binding Assays CompoundSelectivity CB1 IC₅₀ CB2 IC₅₀ CB1 CB2 20 D B 3.93 23 D B 18.43 24 B A61.50 62 D B 9.04 58 D D 1.88 65 D A 25.50 64 D B 7.89 63 D A 24.80 66 DD 1.88 67 D B 20.83 28 C A 266.67 3 D C 1.47 A= <0.10 µM B = 0.10 µM to0.49 µM C = 0.50 µM to 0.99 µM D = ≧1.00 µM

GTPγS Functional Assay Example 15 Membrane Preparation

The membranes were prepared from CHO-K1 cells stably transfected withthe human CB1 receptor (Perkin Elmer, Boston, MA). The cells were grownadherently and maintained in Ham’s F12 medium containing 10% fetalbovine serum (FBS), penicillin, streptomycin and geneticin (G418) at 37°C. in a humid atmosphere of 5% CO₂ following the manufacturer’sinstructions.

For membrane preparation the cells were washed with PBS and scraped offthe plates in cold homogenization buffer (25 mM HEPES (pH 7.4), 2 mMEDTA) containing protease inhibitor cocktail (Sigma Cat.# P8340). Thecell suspension was homogenized with a Polytron and then centrifuged for30 min at 120,000 × g.

G TPγS Assay

GTPʏS binding assay was used for direct measurement of the binding of anon-hydrolysable GTP analog [35S]-GTPyS to the cell membranes containingoverexpressed CB1 or CB2 receptors. Upon receptor activation by anagonist, the G protein is stimulated to bind the non-hydrolysable[35S]GTPyS, allowing [35S]GTPyS-labeled Gα-subunits to accumulatefollowing receptor activation. The bound [35S]GTPyS can be separatedfrom unbound [35S]GTPyS using filtration and quantified by scintillationcounting.

The assays were performed by incubating 5 µg of either CB1 or CB2membrane in a total volume of 100 µl in assay buffer (50 mM Tris-HCl, 5mM MgCl₂, 150 mM NaCl, 1 mM EDTA, 0.05% BSA and 1 mM DTT, pH 7.4)supplemented with 3 µM GDP and 0.05 mg/ml saponin. In each case, thereaction for maximal (stimulated) level of binding contained 0.3 nM[³⁵]GTPʏS and 10 µM CP55,940. Agonist mode was determined, withincreasing concentrations of test compounds in the absence of agonist(CP55,940). Antagonist mode for both CB1 and CB2 contained an EC₆₀concentration of (-)-CP55,940 (12 nM). The basal level of [35S]GTPySbinding was measured in untreated membranes containing no CP55,940 andnon-specific binding (NSB) was determined with 10 µM GTPʏS.

The tested compounds were incubated with membrane/GDP mixture for 30minutes at room temperature before adding 0.3 nM [³⁵]GTPʏS. The finalreaction mixture was incubated at 30° C. for 45 minutes. Incubationswere terminated by rapid vacuum filtration to separate the bound andfree radioligand with Multi Screen 96-well filter plate on aMultiScreen_(HTS) vacuum manifold. Filters were subsequently washed 5times with ice-cold wash buffer containing 50 mM Tris-HCl, pH 7.4 and 5mM MgCl₂. After drying, scintillant was added to each filter. After 1hour, the filter-bound radioactivity was determined by scintillationspectrometry using a 1450 Microbeta scintillation counter (PerkinElmer).

Compounds of the present disclosure were tested in agonist andantagonist mode for both the CB1 and CB2 receptors. The tested compoundswere generally found to exhibit activity in antagonist mode at the CB1and CB2 receptor.

Further Biological Examples Example 16: Simulated Gastric Fluid (SGF)Assay

In a microcentrifuge tube, 626.5 µL of a solution containing 1.1× assaybuffer (37.6 mM NaCl, pH 1.2-1.5) is diluted with 70 µL of a 10× pepsinsolution (Sigma-Aldrich Co. Cat#: P7012, 80,000 U/mL in milliQ water).The resulting solution is incubated at 37° C. and 1,200 rpm in anorbital mixer for 5 minutes, prior to the addition of 3.5 µL of the testcompound (2 mM, DMSO). The sample is incubated in the same conditionsfor as long as required.

At the specified time points, 150 µL aliquots of the sample aretransferred to microcentrifuge tubes containing 24 µL of acid quenchingsolution (0.5 M NaHCO₃). After vortexing the tube for 5 seconds, 348 µLof the protein precipitation solution containing an internal standard(25 µM Glyburide, ACN) are added. The tube is vortexed again for 20seconds, and stored in ice.

Finally, the tubes are centrifuged at 5,000 × g and 4° C. for 15minutes. The percentage remaining of the test compound, compared to timezero, is quantified in the supernatant by HPLC / LC-MS or LC-MS/MS andthe half-life is determined.

Example 17: TRPs Activation: Measurement of Cation Flux ThroughIntracellular Calcium Detection

The transient receptor potential ion channels (TRPs) are non-selectiveligand-gated cation channels that integrate a variety of physical andchemical stimuli. When activated, these channels lead to the gating ofcations, including Ca²⁺, thus generating changes in intracellularcalcium concentration. The single wavelength fluorescent indicatorFluo-4 acetoxymethyl (AM) is used to measure intracellular calcium fluxand concentration in cells expressing TRPs and stimulated withcannabinoids. The Fluo-4 Direct™ calcium assay kit (Molecular Probes,Invitrogen, Carlsbad, CA, USA) allows the direct addition of the reagentinto microplate wells containing cultured cells, without the requirementof media removal or a wash step, therefore facilitating the process oftarget screening.

As adapted from Moriello et al. (“Assay of TRPV1 Receptor Signaling”Methods In Molecular Biology (2016) 1412:65-76, herein incorporated byreference), human embryonic kidney (HEK-293) cells are used to expressdifferent TRPs, including TRPV1 and TRPV2. Cells are grown in Eagle’sMinimum Essential Medium supplemented with 10% fetal bovine serum (FBS),1% penicillin and streptomycin(pen/strep), and maintained in incubatorsat 37° C. in 5% CO₂. Cells are seeded in 96-well plates andpolyethylenimine (PEI) used to transiently transfect HEK-293 cells withexpression vectors containing the open reading frame (ORF) of the TRPsof interest. Transfection using the empty expression vector is performedas a negative control.

24-48 hours after transfection, cells are treated with Fluo-4 Direct™(Molecular Probes) for 30-60 minutes and subsequently exposed tocannabinoids and benchmark compounds for different periods of time.Following incubations, fluorescence is measured using a microplatereader (excitation at 494 nm and emission at 516 nm).

Analysis of data is done by generating nonlinear regression curves andall data points corrected for background fluorescence and negativecontrol. The response of agonists is normalized to the effect of areference agonist and the response of antagonists normalized to the EC₈₀of a reference agonist.

Example 18: PPARy Activation: Nuclear Hormone Receptor Activation Assay

Peroxisome proliferator activated receptors (PPARs) are ligand-activatedtranscription factors of nuclear hormone receptors (NHRs). ThePathHunter® PPARγ protein interaction assay (DiscoverX, Fremont, CA,USA) reports the activation of NHRs based on enzyme complementation ofβ-galactosidase, rendering a chemiluminescent signal.

CHO-K1 PPARγ cell lines (DiscoverX) stably expressing the targetreceptor is used. Cells are grown using reagents provided by themanufacturer (DiscoverX) and maintained in incubators at 37° C. in 5%CO₂. Cells are harvested and plated in black skirt, clear bottom 96-wellplates and allowed to attach and recover overnight. Subsequently, cellsare incubated with cannabinoids and/or benchmark compounds, such astroglitazone and rosiglitazone, for 30-90 minutes at 37° C. in 5 % CO₂.The detection reagent provided by the manufacturer (DiscoverX) is thenadded to the wells, and plates are incubated for 1 hour in the dark,followed by chemiluminescence detection using a microplate reader.Analysis of data is done by generating nonlinear regression curves andall data points are corrected for background luminescence and negativecontrol. The response of agonists is normalized to the effect of areference agonist and the response of antagonists normalized to the EC₈₀of a reference agonist. Basal activity of the cells is set at 0 %.

Numerous references have been made to patents and printed publicationsthroughout this specification. Each of the cited references and printedpublications are individually incorporated herein by reference in theirentirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1-121. (canceled)
 122. A compound having structural formula:

or an enantiomer, diastereomer, racemate, tautomer, or metabolitethereof, or a pharmaceutically acceptable salt, solvate or hydrate ofthe compound, enantiomer, diastereomer, racemate, tautomer, ormetabolite, wherein R¹ is hydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, —CO₂H, -(C₀-C₄ alkyl)-C(O)O(C₁-C₆ alkyl), -(C₀-C₄alkyl)-OC(O)O-(C₁-C₆ alkyl), -(C₀-C₄ alkyl)-N(R^(1b))—C(O)—O—(C₁-C₆alkyl), -(C₀-C₄ alkyl)-O-C(O)-NR^(1b)R^(1c), -(C₀-C₄alkyl)-N(R^(1b))-C(O)-NR^(1b)R^(1c), -OR^(1a), -(C₁-C₄ alkyl)OR^(1a),-SR^(1a), -(C₁-C₄ alkyl)S(O)₀₋₂R^(1a), -NR^(1b)R^(1c), -(C₁-C₄alkyl)NR^(1b)R^(1c), -(C₁-C₄ alkyl)C(O)NR^(1b)R^(1c), -(C₀-C₄alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, or-(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(1a), R^(1b), and R^(1c) areindependently hydrogen, C₁-C₄ alkyl, or -C(O)(C₁-C₄) alkyl; R² ishydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, —CO₂H,-(C₀-C₄ alkyl)-C(O)O(C₁-C₆ alkyl), -(C₀-C₄ alkyl)-OC(O)O-(C₁-C₆ alkyl),-(C₁-C₄ alkyl)OR^(2a), -(C₁-C₄ alkyl)SR^(2a), -NR^(2b)R^(2c), -(C₁-C₄alkyl)NR^(2b)R^(2c), -(C₁-C₄ alkyl)C(O)NR^(2b)R^(2c), -(C₀-C₄alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, or-(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(2a), R^(2b), and R^(2c) areindependently hydrogen, C₁-C₄ alkyl, or -C(O)(C₁-C₄) alkyl; R³ ishydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,—(OCH₂CH₂)₀—₆O(C₁-C₈ alkyl), -(C₀-C₄ alkyl)-NR^(3a)R^(3b), -(C₀-C₄alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl or-(C₀-C₄ alkyl)-heterocycloalkyl, wherein R^(3a) and R^(3b) are eachindependently hydrogen or C₁-C₆ alkyl; R⁴is

wherein R^(4a) is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, -OR^(4e),-(C₁-C₄ alkyl)OR^(4e), -(C₁-C₄ alkyl)-C(O)(C₁-C₄ alkyl), -(C₀-C₄alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl,-(C₀-C₄ alkyl)-heterocycloalkyl, -NR^(4d)R^(4e), or -(C₁-C₄alkyl)NR^(4d)R^(4e), and R^(4b) is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, -CH₂-(OCH₂CH₂)₀₋₆O(C₁-C₈ alkyl), -(C₁-C₄ alkyl)OR^(4e), -(C₁-C₄alkyl)-C(O)(C₁-C₄ alkyl), -(C₁-C₄ alkyl)-C(O)O(R^(4e)), -(C₀-C₄alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl,-(C₀-C₄ alkyl)-heterocycloalkyl, or -(C₁-C₄ alkyl)NR^(4d)R^(4e), whereinR^(4d) is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, -(C₁-C₄alkyl)-C(O)(C₁-C₄ alkyl), -(C₁-C₄ alkyl)-C(O)O(R^(4e)), -(C₁-C₄alkyl)-OC(O)(R^(4e)), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl,-(C₀-C₄ alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl, R^(4e) ishydrogen, C₁-C₄ alkyl, or aryl, and R^(4c) is hydrogen or C₁-C₄ alkyl;R⁵ is hydrogen, C₁-C₈ alkyl, -(C₁-C₄ alkyl)-O-(C₁-C₄ alkyl), -C(O)(C₁-C₄alkyl), -C(O)O(C₁-C₄ alkyl), —C(O)NH₂, -C(O)NH(C₁-C₄ alkyl),-C(O)N(C₁-C₄ alkyl)₂, -(C₁-C₄ alkyl)C(O)O(C₁-C₄ alkyl), or -(C₁-C₄alkyl)OC(O)(C₁-C₄ alkyl); and R⁶ is hydrogen or -OR^(6a), wherein R^(6a)is hydrogen, C₁-C₈ alkyl, -(C₁-C₄ alkyl)-O-(C₁-C₄ alkyl), -C(O)(C₁-C₄alkyl), -C(O)O(C₁-C₄ alkyl), —C(O)NH₂, -C(O)NH(C₁-C₄ alkyl),-C(O)N(C₁-C₄ alkyl)₂, -(C₁-C₄ alkyl)C(O)O(C₁-C₄ alkyl), or -(C₁-C₄alkyl)OC(O)(Ci-C₄ alkyl); wherein each alkyl, alkenyl and alkynyl isunsubstituted, halogenated, substituted with one or two hydroxyl orC₁-C₆ alkoxy groups, or substituted with one or two oxo groups; eachcycloalkyl has 3-10 ring carbons and is saturated or partiallyunsaturated, and optionally includes one or two fused cycloalkyl rings,each fused ring having 3-8 ring members, and is substituted with 0-6 R⁷;each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms whereeach is independently nitrogen, oxygen or sulfur and is saturated orpartially unsaturated, and optionally includes one or two fusedcycloalkyl rings, each having 3-8 ring members, and is substituted with0-6 R⁷; each aryl is a phenyl or a naphthyl, and optionally includes oneor two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkylor heterocycloalkyl ring having 4-8 ring members, and is substitutedwith 0-5 R⁸; each heteroaryl is a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms, where each is independently nitrogen,oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having 1-5heteroatoms where each is independently nitrogen, oxygen or sulfur, andoptionally includes one or two fused cycloalkyl or heterocycloalkylrings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ringmembers, and is substituted with 0-5 R⁸, in which each R⁷ isindependently oxo, C₁-C₄ alkyl, —Cl, —F, —Br, —CN, —SF₅, —N₃, nitro,-SR^(A), -S(O)₁₋₂R^(A), -OR^(A), -(C₀-C₃ alkyl)-OR^(B), -NR^(B)R^(A),-C(O)R^(A), -C(O)NR^(B)R^(A), -NR^(B)C(O)R^(A), -C(S)NRBR^(A),-NR^(B)C(S)R^(A), -CO₂R^(A), -OC(O)R^(A), -C(O)SR^(A), -SC(O)R^(A),-C(S)OR^(A), -OC(S)R^(A), -C(S)SR^(A), -SC(S)R^(A), -S(O)₁₋₂OR^(A),-OS(O)₁₋₂R^(A), -S(O)₁₋₂NR^(B)R^(A), -NR^(B)S(O)₁₋₂R^(A), -OCO₂R^(A),-OC(O)NR^(B)R^(A), -NRBCO₂R^(A), -NR^(B)C(O)NR^(B)R^(A), -SCO₂R^(A),-OC(O)SR^(A), -SC(O)SR^(A), -SC(O)NR^(B)R^(A), -NR^(B)C(O)SR^(A),-OC(S)OR^(A), -OC(S)NR^(B)R^(A), -NR^(B)C(S)OR^(A),-NR^(B)C(S)NR^(B)R^(A), -SC(S)OR^(A), -OC(S)SR^(A), -SC(S)SR^(A),-SC(S)NR^(B)R^(A), -NR^(B)C(S)SR^(A), -NR^(B)C(NR^(B))NR^(B)R^(A),-NR^(B)S(O)₁₋₂NR^(B)R^(A), phenyl, C₃-C₈ cycloalkyl, a five tosix-membered heteroaryl, or a five to six-membered heterocycloalkyl; andeach R⁸ is independently optionally-substituted C₁-C₄ alkyl, —Cl, —F,—Br, —CN, —SF₅, —N₃, nitro, -SR^(A), -S(O)₁₋₂R^(A), -OR^(A), -(C₀-C₃alkyl)-OR^(B), -NR^(B)R^(A), -C(O)R^(A), -C(O)NR^(B)R^(A),-NR^(B)C(O)R^(A), -C(S)NR^(B)R^(A), -NR^(B)C(S)R^(A), -CO₂R^(A),-OC(O)R^(A), —SO₃H,-C(O)SR^(A), -SC(O)R^(A), -C(S)OR^(A), -OC(S)R^(A),-C(S)SR^(A), -SC(S)R^(A), -S(O)₁₋₂OR^(A), -OS(O)₁₋₂R^(A),-S(O)₁₋₂NR^(B)R^(A), -NR^(B)S(O)₁₋₂R^(A), -OCO₂R^(A), -OC(O)NR^(B)R^(A),-NR^(B)CO₂R^(A,) -NR^(B)C(O)NR^(B)R^(A), -SCO₂R^(A), -OC(O)SR^(A),-SC(O)SR^(A), -SC(O)NR^(B)R^(A), -NR^(B)C(O)SR^(A), -OC(S)OR^(A),-OC(S)NR^(B)R^(A), -NR^(B)C(S)OR^(A), -NR^(B)C(S)NR^(B)R^(A),-SC(S)OR^(A), -OC(S)SR^(A), -SC(S)SR^(A), -SC(S)NR^(B)R^(A),-NR^(B)C(S)SR^(A), -NR^(B)C(NR^(B))NR^(B)R^(A),-NR^(B)S(O)₁₋₂NR^(B)R^(A); phenyl, C₃-C₈ cycloalkyl, a five tosix-membered heteroaryl, or a five to six-membered heterocycloalkyl;wherein each R^(A) is independently H or C₁-C₃ alkyl, and each R^(B) isindependently H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ hydroxyalkyl,-S(O)₁₋₂(C₁-C₃ alkyl), -C(O)(C₁-C₃ alkyl) or -CO₂(C₁-C₃ alkyl), or R^(A)and R^(B) together with the nitrogen atom to which they are attachedcome together to form an unsubstituted heterocycloalkyl ring comprisedof 3-6 ring members.
 123. The compound according to claim 122, whereinR¹ is hydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, —CO₂H, -(C₀-C₄alkyl)-C(O)O(C₁-C₆ alkyl), -(C₀-C₄ alkyl)-N(R^(1b))—C(O)—O—(C₁-C₆alkyl), -(C₀-C₄ alkyl)-O-C(O)-NR^(1b)R^(1c), -(C₀-C₄alkyl)-N(R^(1b))-C(O)-NR^(1b)R^(1c), -OR^(1a), -(C₁-C₄ alkyl)OR^(1a),-SR^(1a), -(C₁-C₄ alkyl)SR^(1a), -NR^(1b)R^(1c), -(C₁-C₄alkyl)NR^(1b)R^(1c), -(C₁-C₄ alkyl)C(O)NR^(1b)R^(1c),-(C₀-C₄alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, or-(C₀-C₄ alkyl)-heterocycloalkyl.
 124. The compound according to claim122, wherein R² is hydrogen, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, —CO₂H,-(C₀-C₄ alkyl)-C(O)O(C₁-C₆ alkyl), -(C₁-C₄ alkyl)OR^(2a), -(C₁-C₄alkyl)SR^(2a), -NR^(2b)R^(2c), -(C₁-C₄ alkyl)NR^(2b)R^(2c), -(C₁-C₄alkyl)C(O)NR^(2b)R^(2c), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄ alkyl)-heteroaryl,-(C₀-C₄ alkyl)-cycloalkyl, or -(C₀-C₄ alkyl)-heterocycloalkyl.
 125. Thecompound according to claim 122, wherein R³ is hydrogen, C₁-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, -(OCH₂CH₂)₀₋₆OCH₃, -(C₀-C₄ alkyl)-aryl,-(C₀-C₄ alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl or -(C₀-C₄alkyl)-heterocycloalkyl.
 126. The compound according to claim 122,wherein the compound is of formula:

or

.
 127. The compound according to claim 122, wherein R⁵ is hydrogen,C₁-C₆ alkyl, -(C₁-C₄ alkyl)-O-(C₁-C₄ alkyl), -C(O)(C₁-C₄ alkyl),-C(O)O(C₁-C₄ alkyl), —C(O)NH₂, -C(O)NH(C₁-C₄ alkyl), or -C(O)N(C₁-C₄alkyl)₂.
 128. The compound according to claim 122, wherein R⁶ ishydrogen or -OR^(6a), wherein R^(6a) is hydrogen, C₁-C₆ alkyl, -(C₁-C₄alkyl)-O-(C₁-C₄ alkyl), -C(O)(C₁-C₄ alkyl), -C(O)O(C₁-C₄ alkyl),—C(O)NH₂, -C(O)NH(C₁-C₄ alkyl), or -C(O)N(C₁-C₄ alkyl)₂.
 129. Thecompound according to claim 122, wherein R⁴ is

or

..
 130. The compound according to claim 122, wherein R^(4a) is C₁-C₈alkyl, C₂-C₈ alkenyl, -OR^(4e), -(C₁-C₄ alkyl)OR^(4e), -(C₁-C₄alkyl)-C(O)(C₁-C₄ alkyl), -(C₀-C₄ alkyl)-aryl, -(C₀-C₄alkyl)-heteroaryl, -(C₀-C₄ alkyl)-cycloalkyl, -(C₀-C₄alkyl)-heterocycloalkyl, -NR^(4d)R^(4e), or -(C₁-C4 alkyl)NR^(4d)R^(4e).131. The compound according to claim 122, wherein each alkyl isunsubstituted.
 132. The compound according to claim 122, wherein each R⁷is independently oxo, C₁-C₄ alkyl, —Cl, —F, —Br, —CN, —SF₅, —N₃, nitro,-SR^(A), -S(O)₁₋₂R^(A), -OR^(A), -NR^(B)R^(A), -C(O)R^(A),-C(O)NR^(B)R^(A), -NR^(B)C(O)R^(A), -C(S)NR^(B)R^(A), -NR^(B)C(S)R^(A),-CO₂R^(A), -OC(O)R^(A), -C(O)SR^(A), -SC(O)R^(A), -C(S)OR^(A),-OC(S)R^(A), -C(S)SR^(A), -SC(S)R^(A), -S(O)₁₋₂OR^(A), -OS(O)₁₋₂R^(A),-S(O)₁₋₂NR^(B)R^(A), or -NR^(B)S(O)₁₋₂R^(A).
 133. The compound accordingto claim 122, which is:3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonicacid; sodium3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonate;2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(methylsulfonyl)-5-pentylbenzene-1,3-diol;4-(cyclopropylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;4-(tert-butylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;4-(benzylsulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(phenylsulfonyl)benzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-4-((4-nitrophenyl)sulfonyl)-5-pentylbenzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(pyridin-3-ylsulfonyl)benzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(furan-3-ylsulfonyl)-5-pentylbenzene-1,3-diol;4-((1H-imidazol-4-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(oxetan-3-ylsulfonyl)-5-pentylbenzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-((perfluorophenyl)sulfonyl)benzene-1,3-diol;4-((3-(3,7-dimethylocta-2,6-dien-l-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)cyclohexan-1-one;1-(2-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)ethyl)pyrrolidine-2,5-dione;4-((2-(dimethylamino)ethyl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;1-(3-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)piperidin-1-yl)ethan-1-one;4-((2-chloropyrimidin-5-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-methyl-6-pentylbenzenesulfonamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N,N-dimethyl-6-pentylbenzenesulfonamide;N-cyclopropyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-isopropyl-6-pentylbenzenesulfonamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-phenylbenzenesulfonamide;N-benzyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;2-(3,7-dimethylocta-2,6-dien-1-yl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyrimidin-2-yl)benzenesulfonamide;4-((4-methylpiperazin-1-yl)sulfonyl)-5-pentylbenzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentyl-4-(piperidin-1-ylsulfonyl)benzene-1,3-diol;2-(3,7-dimethylocta-2,6-dien-1-yl)-4-(morpholinosulfonyl)-5-pentylbenzene-1,3-diol;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyridin-3-yl)benzenesulfonamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-(2-oxopropyl)-6-pentylbenzenesulfonamide;1-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)azetidin-3-one;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-N-(oxetan-2-ylmethyl)-6-pentylbenzenesulfonamide;4-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;4-((2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol;((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)alanine;methyl((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)alaninate;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-morpholinopropanamide;4-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonamido)-4-oxobutanoicacid;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-(4-methylpiperazin-1-yl)propanamide;2-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(2-methoxyethoxy)acetamide;2-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-hydroxypropanamide;2-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)propanamide;3-amino-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-methylpropanamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-3-oxobutanamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(3-methyl-1H-1,2,4-triazol-5-yl)acetamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-1H-1,2,4-triazole-5-carboxamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)oxetane-2-carboxamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)benzamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)nicotinamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-phenylacetamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(furan-2-yl)acetamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(oxazol-2-yl)acetamide;N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)-2-(thiazol-2-yl)acetamide;2-(1H-benzo[d]imidazol-2-yl)-N-((3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylphenyl)sulfonyl)acetamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(phenylsulfonyl)benzamide;N-(cyclohexylsulfonyl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-((prop-1-en-1-yl)sulfonyl)benzamide;N-((1H-benzo[d]imidazol-2-yl)sulfonyl)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzamide;N-cyclohexyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;N-cyclobutyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-N-hexyl-2,4-dihydroxy-6-pentylbenzenesulfonamide;N-allyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonamide;3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentyl-N-(pyridin-3-ylsulfonyl)benzamide;orphenyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzenesulfonate.134. A pharmaceutical composition comprising a compound according toclaim 122, or an enantiomer, diastereomer, racemate, tautomer, ormetabolite thereof, or a pharmaceutically acceptable salt, solvate orhydrate of the compound, enantiomer, diastereomer, racemate, tautomer,or metabolite, together with a pharmaceutically acceptable excipient,diluent, or carrier.
 135. A method of treating a disease associated witha cannabinoid receptor in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound according to claim 122 or a pharmaceuticalcomposition thereof.
 136. The method according to claim 135, wherein thecannabinoid receptor is one or more of CB1, CB2, 5HT1A, 5HT2A, GPR18,GPR55, GPR119, TRPV1, TPRV2, PPARy or a µ-opioid receptor.
 137. Themethod according to claim 135, wherein the cannabinoid receptor is CB1or CB2.
 138. A method of treating a disease in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound according to claim 122 ora pharmaceutical composition thereof, wherein the disease is acute pain,ADHD/ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer’s,anorexia, anxiety disorders, arthritis, atherosclerosis, autism, bipolardisorder, bums, cancer, cancer pain, Charcot-Marie-Tooth disease,chronic inflammatory demyelinating polyneuropathies, chronic pain,chronic allograft nephropathy, cocaine use disorder, complex regionalpain syndrome, congestive heart failure, depression, fibromyalgia,fragile X syndrome/FXTAS, frontotemporal dementias, gingivitis pyrexia,glaucoma, glioblastoma, glomerulonephropathy, Huntington’s disease,hypertrophic scars, IBD/IBS, inflammation, Inflammatory myopathies,ischemia, kidney fibrosis, keloids, leukodystrophies, liver fibrosis,liver cirrhosis, lung fibrosis, migraine, multiple sclerosis, myocardialinfarction, nausea, neuropathic pain, nightmare disorder, non-alcoholicfatty liver disease, obesity, obsessive-compulsive disorder, opioidsparing, opioid use disorder, osteoarthritis, osteoporosis, Parkinson’s,post-concussion syndrome/traumatic brain injury,psychosis/schizophrenia, PTSD, regulation of bone mass, REM sleepbehaviour disorder, reperfusion injury, Rett syndrome, rheumatoidarthritis, skin conditions, sleep disorders, spinocerebellar ataxias,systemic fibrosis, systemic sclerosis, thermal injury, tobacco usedisorder/nicotine dependence, Tourette’s, tumors, or trigeminalneuralgia.